- Email: [email protected]
sphingosine 1-phosphate signalling in central nervous system
Cellular Signalling 21 (2009) 7–13
Contents lists available at ScienceDirect
Cellular Signalling j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c e l l s i g
Review
Sphingosine kinase/sphingosine 1-phosphate signalling in central nervous system Taro Okada, Taketoshi Kajimoto, Saleem Jahangeer, Shun-ichi Nakamura ⁎ Division of Biochemistry, Department of Biochemistry/Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
a r t i c l e
i n f o
Article history: Received 31 March 2008 Received in revised form 4 July 2008 Accepted 17 July 2008 Available online 22 July 2008 Keywords: Sphingosine 1-phosphate Sphingosine kinase Neurotransmitter Alzheimer's disease Neuron Central nervous system Apoptosis
a b s t r a c t Sphingolipids were once regarded as inert structural components of cell membranes. Now these metabolites are generally believed to be important bioactive molecules that control a wide repertoire of cellular processes such as proliferation and survival of cells. Along with these ubiquitous cell functions observed in many peripheral tissues sphingolipid metabolites, especially sphingosine 1-phosphate, exert important neuronspecific functions such as regulation of neurotransmitter release. This review summarizes physiological and pathological roles of sphingolipid metabolites emphasizing the role of sphingosine 1-phosphate in the central nervous system. © 2008 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
6. 7.
Introduction . . . . . . . . . . . . . . . Sphingolipid metabolism . . . . . . . . . SphK . . . . . . . . . . . . . . . . . . Mode of actions of S1P . . . . . . . . . . SphK/S1P signalling in CNS . . . . . . . . 5.1. Neurite extension and retraction . . 5.2. Proliferation, survival and apoptosis 5.3. Neurotransmitter release . . . . . Sphingolipids and neuronal disease . . . . Perspectives . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
7 8 8 9 10 10 10 10 11 12
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
1. Introduction Sphingolipids have long been regarded as structural components of cell membranes. Increased attention has been paid to sphingolipid metabolism following the discovery that protein kinase C could be inhibited by the sphingolipid metabolite sphingosine [1]. The physiological roles of ceramide as intracellular biomodulator
Abbreviations: S1P, Sphingosine 1-phosphate; SphK, Sphingosine kinase; PMA, Phorbol 12-myristate 13-acetate; TNFα, Tumor necrosis factor α; EGF, Epidermal growth factor; ERK, Extracellular signal-regulated kinase; S1P1–5, S1P receptor type 1–5; PA, Phosphatidic acid; PLD, Phospholipase D; AD, Alzheimer's disease; Aβ, amyloid β-peptide. ⁎ Corresponding author. Tel.: +81 78 382 5420; fax: +81 78 382 5439. E-mail address: [email protected] (S. Nakamura). 0898-6568/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2008.07.011
were then highlighted by the observation that sphingomyelin hydrolysis and ceramide generation could be triggered by diverse stimuli in a wide variety of cell types [2]. It has now become clear that once ceramide is generated from sphingomyelin, it can be converted into a number of other bioactive sphingolipids, including ceramide 1-phosphate, sphingosine and sphingosine 1-phosphate (S1P). Ceramide regulates stress responses by inducing growth arrest or apoptosis, whereas S1P promotes cell proliferation and cell survival and the dynamic balance between these two signalling bioactive lipids, termed sphingolipid rheostat, determines cell's fate either to survive or to die [3]. The role of sphingolipid metabolites in neuronal tissues was studied mainly based on an analogy of the results obtained in nonneuronal systems. Recent observations, however, clearly show that
8
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
sphingomyelin metabolite S1P additionally exerts its neuron-specific role, e.g., regulation of neurotransmitter release. This review summarizes the neuronal functions of sphingolipid metabolites with emphasis on S1P and sphingosine kinase (SphK), a key enzyme for the production of S1P, and discusses its role in neuronal disorders. 2. Sphingolipid metabolism Sphingolipids are a class of complex lipids containing an amidelinked fatty acid and a long-chain (sphingoid) base that are important structural components of cell membranes. Different combinations of sphingoid bases, fatty acids and head group moieties lead to a large number of sphingolipids and glycosphingolipids. De novo synthesis of sphingolipids is initiated by the condensation of serine and palmitate through a complex series of synthetic pathways [4]. Cell signalling through sphingolipids starts from the degradation of sphingomyelin by sphingomyelinases under various cellular environments such as exposure to inflammatory cytokine stimulation and stress [5]. Once ceramide is generated it can be converted into a number of bioactive sphingolipids, including ceramide 1-phosphate, sphingosine, and S1P [6–8]. Sphingosine and ceramide are generally considered to inhibit cell proliferation. For example, treatment of RIE cells with sphingosine has been shown to suppress retinoblastoma (Rb) protein phosphorylation and Cdk4 protein expression levels [9] thus suppressing cell proliferation. Similarly, ceramide is reported to activate the stress-activated protein kinases (SAPKs, also known as Jun nuclear kinases or JNKs) [10]. However ceramide can also activate a novel signal transduction/cell survival pathway involving tyrosine kinases (e.g. PDGF receptor kinase), phosphoinositide 3-kinase (PI3K) and PKC to promote c-Raf dependent activation of the p42/p44 MAPK cascade [11]. This ability of ceramide to exploit PI3K-dependent signalling suggests that ceramide might be antiapoptotic at least in some cells [11]. Cellular levels of S1P are regulated by the concerted action of the enzymes responsible for its formation and degradation (Fig. 1). S1P is biosynthesized through the phosphorylation of sphingosine via SphK and its metabolic fate includes the irreversible cleavage to transhexadecenal and ethanolamine phosphate by a pyridoxal phosphate-
dependent lyase [12], or the hydrolytic removal of the phosphomonoester group by S1P phosphatase or lipid-phosphate phosphatases [13–15]. 3. SphK SphKs are members of lipid kinases and are evolutionarily well conserved, holding common sequences in protozoa, yeast, plants and mammals [16,17]. Two mammalian isoforms of SphK, SphK1 and SphK2 with molecular masses of 43 and 65 kDa, respectively, have been identified through molecular cloning [18–20]. Almost all of the SphK1 sequence aligns with a region of the SphK2 sequence, with an 80% similarity [21]. SphK2, however, also possesses two additional divergent sequences at its N terminus and in the middle of its sequence, suggesting distinct biological functions. Indeed, it has been shown that exogenously expressed SphK1 causes cell proliferation [22] whereas SphK2 overexpression results in inhibition of proliferation [23] or in apoptosis [24,25]. In addition, down-regulation of SphK1 by siRNA treatment has also been shown to activate proapoptotic events in the cells such as translocation of Bax/Bcl-2 to mitochondria and its oligomerization, mitochondrial membrane permeabilization (MMP), release of cytochrome c and activation of executioner caspase 7 [26]. Correspondingly, the two isoforms show quite distinct patterns of subcellular distribution. SphK1 is distributed exclusively in the cytoplasm [22] due to extensive export from the nucleus by its nuclear export signal activity [27]. On the other hand, SphK2 possesses a nuclear import signal as well as nuclear export signals and shuttles between the nucleus and cytoplasm depending on cellular conditions, i.e., it enters the nucleus under the conditions of high cell density [23] or stress such as serum removal [25] and stops proliferation or induces apoptosis. There are several possible mechanisms underlying SphK2-induced apoptosis, e.g., S1P produced within the nucleus catalyzed by SphK2 might induce apoptosis through as yet unidentified intranuclear mechanisms or increased ceramide level in the cytoplasm as a result of SphK2 sequestration in the nucleus may induce apoptosis. There is also a report that SphK2induced apoptosis through a motif similar to that present in Bcl-2-
Fig. 1. Pathways of sphingolipid metabolism. The pathway of sphingolipid metabolism is depicted emphasizing bioactive lipid mediators ceramide and S1P. Although intracellular actions of S1P are poorly defined, the mechanism underlying S1P receptor-mediated actions is becoming clearer.
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
homology domain 3 (BH3)-only proteins, a pro-apoptotic subgroup of the Bcl-2 family, although mutation of the conserved leucines present in BH3 domains in SphK2 caused only partial reduction of SphK2induced apoptosis [24]. SphKs exhibit substantial basal activity since recombinant enzymes expressed in Escherichia coli thus containing no mammalian modifications exhibit enzyme activity comparable to that prepared from mammalian expression systems [28]. Therefore, spatio/temporal changes in compartmentalization of the enzymes may play a determinant role in the regulation of SphK/S1P-mediated signalling. SphKs do not have obvious membrane-anchoring sequences and usually behave as soluble enzymes under basal conditions, however upon stimulation SphKs are known to undergo activation and translocation by mechanisms involving protein phosphorylation, protein–lipid binding, protein–protein interaction, and calcium/ calmodulin (see e.g., [29]). Several agonists such as phorbol 12-myristate 13-acetate (PMA) or TNFα have been shown to cause an extracellular signal-regulated kinase (ERK)-dependent phosphorylation of SphK1 at Ser-225, which is important for subsequent translocation of the enzyme to the plasma membrane [30]. Similarly, PMA or EGF induces an ERK-dependent phosphorylation of SphK2 at Ser-351 and Thr-578 that is important for EGF-stimulated migration of MDA-MB-453 cells [31]. Another line of evidence suggests that PMA treatment results in a protein kinase D-mediated phosphoryaltion of SphK2 at Ser-419 and Ser-421 in the nuclear export signal sequence and subsequent export of the enzyme from the nucleus [32]. In addition to the regulation by phosphorylation membrane recruitment of SphK1 may also involve protein–lipid interactions. The conserved residues Thr-54 and Asn-89 in the putative membranebinding surface of SphK1 are essential for selective binding of the enzyme to phosphatidylserine and membrane targeting [33]. The same study also suggested that phosphorylation of SphK1 at Ser-225 enhances the membrane affinity and plasma membrane selectivity of SphK1, presumably by modulating the interaction of Thr-54 and Asn89 with the membrane. Besides phosphatidylserine, phosphatidic acid (PA) produced by phospholipase D (PLD) has been proposed to be a factor to affect SphK cellular distribution. The membranes enriched in PA may be physiologically important sites of S1P production [34]. It has been reported that SphK1 interacts directly with PA and this high affinity interaction is responsible for the translocation/localization of SphK1 to the Golgi apparatus and early endosomes in cells where PLD1 has been induced. The colocalization of SphK1 and PLD1, under conditions of PLD1 activation has led to the idea that SphK1 is a downstream effector of PA [34]. In addition to binding, PA has been proposed to enhance the enzyme activity of SphK [28,35]. Protein–protein interaction also plays roles in recruiting SphKs to specialized compartments in the cells. The activation of SphK1 at the membrane by TNFα requires its interaction with the adapter molecule TRAF2 [36]. Interestingly, while protein–protein interaction is required for SphK1 activation by TNFα, it is not necessary for the activation of the enzyme by PMA, suggesting that although both agonists induce translocation of SphK1 to the membranes by an ERK-dependent phosphorylation of Ser-225, the activation of SphK1 at the membrane occurs by distinct mechanisms. The interaction of SphK1 with another adopter molecule, RPK118, is important for the localization of the enzyme at early endosomes [37]. RPK118 contains a PX domain that specifically binds to phosphatidylinositol 3-phosphate, a unique lipid which is enriched in early endosomes, thus recruiting SphK1 to early endosomes and presumably regulating vesicular trafficking. In addition, it has been reported that SphK1 directly interacts with the src family tyrosine kinase Lyn (in vivo as well as in vitro) and this leads to the recruitment of SphK to the high affinity FcɛRI during immunoglobulin E (IgE) dependent mast cell activation, an interaction that leads to the enhancement of lipid and tyrosine kinase activity in sphingolipidenriched rafts [29].
9
Calcium also regulates SphK activity as well as its subcellular localization. SphK1 possesses putative calcium/calmodulin binding motifs, and the enzyme binds to a calmodulin affinity column in the presence of calcium [38]. Involvement of calcium in the regulation of SphK has been suggested by several studies. Membrane depolarization causes SphK activation by a mechanism sensitive to the Ca2+ channel blocker verapamil, suggesting that calcium influx from intracellular stores by the voltage-gated Ca2+ channel mediates SphK activation [39]. Calcium mobilization from intracellular stores by the Ca2+-ATPase inhibitor thapsigargin activates SphK [40]. Attenuation of calcium levels by the calcium chelator BAPTA/AM inhibits S1P formation in response to the activation of muscarinic, formyl peptide, and P2Y2 purinergic receptors [41]. The importance of phospholipase C in producing transient calcium signals to activate SphK was emphasized by Olivera et al. where a mutation in the phospholipase C binding domain of the platelet-derived growth factor receptor abrogates SphK activation [42]. More recently it has been shown that an SphK1 mutant, which lacks the ability of calmodulin binding, failed to undergo agonist-dependent translocation to plasma membrane [43]. Although several lines of evidence indicate the involvement of calcium signal in the activation of SphK, calcium/calmodulin has no effect on the enzyme activity in vitro [28], suggesting the participation of other molecule(s) in the calcium-dependent SphK activation. 4. Mode of actions of S1P S1P is found in high concentrations in human serum (0.5 µM) [44]. Recently, it has been reported that erythrocytes might be the major contributors of S1P in serum [45–47]. S1P exerts several effects on cells including proliferation, survival, regulation of cell motility, and cytoskeletal reorganization. Most of the effects are mediated by the interaction of S1P with the cell surface S1P receptors as well as the intracellular action of S1P as a second messenger (Fig. 1). Although the mechanism of intracellular action of S1P has not been clearly understood, it is believed that S1P is involved in calcium homeostasis in various cells. S1P induces Ca2+ release from microsomal membrane vesicles enriched in rough endoplasmic reticulum [48,49]. Photolysis of intracellular caged S1P causes calcium mobilization independently of G-protein-coupled receptors in HEK-293, SKNMC and HepG2 cells [50]. On the other hand, SphK pathway is also involved in the regulation of calcium channels. Sphingosine inhibits voltage-operated calcium channel in pituitary GH4C1 cells [51] and SphK regulates the function of the channel by removal of the substrate sphingosine [52]. Sphingosine also inhibits calcium releaseactivated calcium current (ICRAC) through direct block of ICRAC channels [53]. Furthermore Itagaki and Hauser proposed that S1P is a calcium influx factor linking calcium store depletion to downstream store-operated calcium entry (SOCE) [54]. Involvement of S1P in the SOCE pathway has also been reported in chick retinal neurons [55]. The binding of S1P to the S1P receptors activates different signalling pathways involving heterotrimeric G proteins which, in turn, control adenylate cyclase, phospholipases C an D, phosphoinositide 3-kinase, c-Jun N-terminal kinase, ERK, p38, small GTPases such as Rac and Rho and probably non-receptor protein-tyrosine kinases and tyrosine phosphatases [56–58]. Importantly, intracellularly generated S1P resulting from activation of SphK can be exported out of cells and functions as a ligand for S1P receptors [59,60] to regulate a wide variety of cellular responses. For example, S1P receptor type 1 (S1P1) is needed in T and B cells for their egress from the thymus and secondary lymphoid organs [61]. In mast cells cross-linking of FcγRI has been shown to activate SphK and increase S1P secretion, leading to autocrine/paracrine activation of S1P1, which is important for their migration toward antigen, and S1P2, which regulates their degranulation [62]. It has recently been demonstrated that intracellular S1P produced upon FcγRI crosslinking is exported out of mast cells at least in part by an ATP binding
10
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
cassette transporter, ABCC1, independently of their degranulation [63], suggesting an autocrine/paracrine action of S1P. In addition, S1P receptor activation of neurons has been shown to play an important role in the potentiation of neurotransmitter release (see below). 5. SphK/S1P signalling in CNS 5.1. Neurite extension and retraction Neurite extension and retraction are important processes in the establishment of neuronal networks during development and are largely regulated by the organization of the actin cytoskeleton controlled by the balance between the opposing actions of the small GTPases, Rho and Rac [64]. Although Rho induces collapse of growth cones and inhibition of neurite outgrowth [65], Rac is required for neurite outgrowth [66]. Of interest, in diverse cell types, S1P receptors differentially regulate Rac and Rho. Generally, binding of S1P to S1P1 causes Rac activation, whereas S1P2 results in Rho activation (reviewed in [67]). For example, addition of S1P to PC12 cells transiently expressing S1P2 caused cell rounding [68] and similarly, downregulation of S1P2 by antisense oligonucleotides has been shown to enhance neurite extension and prevent S1P-induced rounding in PC12 cells [69]. Moreover, treatment of PC12 cells with NGF causes SphK1 activation and subsequent translocation from the cytosol to the plasma membrane to generate S1P in a spatially and temporally restricted manner [70]. This S1P binds to and activates S1P1 on the cell surface, leading to the activation of signalling pathways important for neurite extension. Similarly, glial cell line-derived neurotrophic factor/RET signalling transactivates SphK/S1P signalling and induces neurite extension through S1P1 receptor [71]. Molecular mechanisms underlying neurotropic factor-induced SphK activation remain to be clarified. Furthermore, SphK/S1P signalling system may be involved in axon guidance in the Xenopus visual system. Strochlic et al. showed that S1P induces rapid collapse and repulsive turning of Xenopus retinal neuron through S1P5 and that gain or loss of SphK–S1P pathway in vivo causes errors in axon navigation [72]. 5.2. Proliferation, survival and apoptosis Neurogenesis in central nervous system is essential for creating neuronal networks during embryonic development as well as in some areas of adult brain such as hippocampal formation. By analogy to roles of S1P observed mostly in non-neuronal cells it has been considered that S1P plays roles in neuronal proliferation. To support this idea, expression of S1P1 receptor is prominent both in cerebral cortical proliferative zone and in ventricular areas of the mesencephalon and coincides with the period of neurogenesis [73]. In addition, embryonic S1P1-null mice die before most neurons are generated [74]. In an in vitro study S1P has been shown to stimulate neural stem/progenitor cell proliferation through a Gi-coupled receptor and promotes their differentiation into neurons and astrocytes in an S1P receptor-mediated fashion [75]. Furthermore, physiological importance of SphK/S1P signalling in neurogenesis has been demonstrated by using SphK1/SphK2 double-knockout mice as well as S1P1 receptor-null mice showing severely disturbed neurogenesis resulting in embryonic lethality [76]. While neuronal survival is essential for the maintenance of the neuronal circuits that ensure the proper functioning of the postmitotic neurons in the adult, it is also known that apoptosis is a physiological event in the development of the mammalian nervous system. Loss of neurons is an important adaptive mechanism for establishing functional neuronal populations and to guarantee the elimination of neurons that contact inappropriate targets. Thus neuronal survival and apoptosis are reciprocal and physiologically important processes for the maintenance and remodeling of postmitotic neuronal functions. For the regulation of neuronal survival
and apoptosis sphingolipids especially ceramide and S1P play an important role. Generally, cellular effects of ceramide and S1P are different depending on cell types, concentrations of these lipids, and developmental stages. In hippocampal neurons at immature stages exogenous ceramide promotes survival at low concentrations although it triggers cell death at concentrations higher than 5 µM [77]. Interestingly, mature hippocampal neurons undergo nonnecrotic cell death at the same low concentrations of ceramide. Ceramide provided to sensory neurons protects from NGF withdrawal-induced apoptosis, however, the actual lipid mediator seems to be its metabolites since in the presence of the ceramidase inhibitor N-oleoyl-ethanolamine, ceramide induces apoptosis [78]. Similarly, in mesencephalic neurons inhibition of the conversion of ceramide into S1P by dimethylsphingosine blocks the protection against excitotoxicity [79]. More recently importance of S1P signalling in cell survival has been shown using S1P receptor-null mice. S1P2 receptor-knockout mice display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness suggesting that S1P2 receptor-mediated signal is essential for survival of hair cells and proper functioning of the auditory and vestibular systems [80–82]. 5.3. Neurotransmitter release Sphingolipid metabolites such as ceramide, sphingosine and S1P have been proposed to be involved in the regulation of neurotransmitter release. For example, sphingosine inhibits voltage-activated calcium channels in pituitary cells [51]. Ceramide also inhibits L-type Ca2+ channels in rat pinealocytes [83]. However it is not clear whether these effects are mediated by the lipid or the further metabolites. The possible involvement of S1P in neurotransmitter release was further suggested by several lines of evidence. Alemany et al. have shown that depolarization induces rapid and transient formation of intracellular S1P in PC12 cells and have postulated that the rise in S1P concentration during depolarization may contribute to depolarization-induced noradrenaline release and Ca2+ increase in these cells [39]. The contribution of S1P in neuronal excitability was strongly suggested by the observation that S1P2-null mice have spontaneous seizures and display significant increases in excitatory postsynaptic currents [84] although precise mechanism underlying the involvement of the S1P receptor in neuroexcitability is unknown. Furthermore, in developing cerebellar neurons NGF induces glutamate release and release of Ca2+ from ryanodine receptor via its p75 neurotrophin receptor where ceramide generation by sphingomyelinase activation seems to be necessary since scyphostatin, a sphingomyelinase inhibitor, blocks the NGF-dependent Ca2+ increase and glutamate release [85]. Similarly, NGF can increase the excitability of nociceptive sensory neurons through activation of the p75 receptor and its consequent liberation of ceramide from sphingomyelin [86] and the same group has subsequently shown that intracellular S1P derived from ceramide acts as an internal second messenger to suppress the outward K+ currents (IK), which enhances the excitability of the sensory neurons; however, the effector system whereby S1P modulates IK remains undetermined [87]. S1P receptor-mediated regulation of neurotransmitter release was further demonstrated in hippocampal neurons. S1P is involved in glutamate secretion from hippocampal neurons through an autocrine/paracrine action: S1P at a nanomolar concentration by itself elicits glutamate secretion from hippocampal neurons even when the Na+-channel is blocked by tetrodotoxin, while S1P at a picomolar level potentiates depolarization-evoked glutamate secretion. Importantly, depolarization causes the activation of S1P1 on the presynapses of hippocampal neurons, which is inhibited by the knockdown of SphK1 [88] (Fig. 2) although mechanisms underlying S1P-induced neurotransmitter release remain to be clarified. Furthermore SphK inhibitors such as dimethylsphingosine and 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
11
Fig. 2. Current model of mechanism underlying neurotransmitter release from presynaptic nerve terminal via SphK/S1P signalling pathway. During depolarization SphK1 is activated by an unidentified mechanism and is translocated from the cytosol to membranes at puncta or boutons of presynaptic neurons and produces S1P in close proximity to where S1P1 receptor is present. S1P may be transported via ATP binding cassette transporter, ABCC1 and activate S1P1, which may facilitate the enhancement or induction of neurotransmitter release depending on S1P concentrations produced [74].
thiazole significantly decreased the rate of spontaneous AMPAminiature excitatory postsynaptic currents for CA3 pyramidal neurons in hippocampal slices prepared from adult rats [89], indicating that S1Pelicited spontaneous AMPA secretion may be relevant in adult rat hippocampal functions. The notion that SphK/S1P signalling plays an important role in the regulation of neurotransmitter release is important for the understanding of molecular mechanisms underlying synaptic transmission of signals as well as synaptogenesis. Consistent with the observation that spontaneous AMPA-miniature excitatory postsynaptic currents were observed in CA3 but not in CA1 pyramidal neurons in hippocampal slices in adult rats, immunohistochemical analysis showed that SphK1 was enriched in mossy fibers from granular cells in the dentate gyrus, projecting towards CA3 pyramidal neurons in the hippocampus, but the enzyme was undetectable in Schaffer collaterals from CA3 pyramidal neurons projecting towards CA1 pyramidal neurons [89]. For the hippocampus of the adult rat thousands of new granule cells are generated per day [90]. The ongoing neurogenesis in the adult has recently been implicated in the formation of hippocampus-dependent memories such as tracing memory conditions [91]. The mechanisms of synaptogenesis of newly produced neurons with preexisting neuronal networks during adult neurogenesis as well as synaptogenesis which occurred in the developmental stages are largely unexplored yet. The observation that SphK1/SphK2 double-knockout mice as well as S1P1 receptornull mice show severe defects in neuronal development including neural tube closure shows pivotal role of SphK/S1P signalling system in the central nervous system development [76]. Recent observations support the notion that S1P is one of the important determinants for triggering spontaneous secretion of neurotransmitters such as glutamate [88,89]. Further studies on the role of S1P in the synaptogenesis in hippocampal neurons may facilitate the understanding of memory formation and learning. It is also important to clarify whether this concept is applicable to other neurotransmitter systems in various brain regions.
6. Sphingolipids and neuronal disease Although apoptosis along with proliferation/survival are essential for neuronal tissue maintenance and remodeling, inappropriate activation of apoptosis may contribute to neurodegenerative disorders such as Alzheimer's disease (AD) [92]. The progressive impairment of short-term memory and emotional disturbances that characterizes AD result from the dysfunction and death of neurons in the hippocampus and associated regions of the cerebral cortex and limbic system. Although the pathogenesis of AD is not completely understood, accumulation of the amyloid β-peptide (Aβ) is postulated to cause neuronal degeneration in AD brains [93–95]. In addition, studies in human neurons [96], oligodendrocytes [97] and brain sections [98] provide direct evidence that the Aβ peptide that accumulates in AD causes neutral sphingomyelinase activation and subsequent ceramide accumulation. Since it is becoming apparent that oxidative stress and ceramide generation are intimately connected in cell death signalling [99–101], oxidative stress and excessive production and accumulation of Aβ may cause neuronal cell death through abnormal sphingolipid metabolism. In addition to neurodegenerative disorders sphingolipid metabolites such as S1P may have profound effects on neuronal diseases related to increased excitability. To support this possibility S1P seems to have a role in the modulation of neuronal excitability since S1P2 receptor-null mice have spontaneous seizures and display significant increase in excitatory postsynaptic currents. These mice displayed no apparent anatomical or physiological defects, however, they showed spontaneous and sporadic seizures between 3 and 7 weeks of age. Although precise mechanism underlying increased neuronal excitability in these mice remains unknown, this is suggestive of potential causal relationship between S1P and neuronal excitability. Recent observations that NGF-induced production of S1P causes neuronal excitability in sensory neurons [87] and that S1P produced under basal conditions or during depolarization causes spontaneous or potentiation of glutamate release from hippocampal neurons, respectively [88] indicate that sphingolipid metabolites
12
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
play a pivotal role in neuron-specific function such as neurotransmitter secretion in the central nervous system in addition to other roles such as proliferation, survival, and apoptosis seen in peripheral tissues. The ability of S1P to cause neuronal excitability may not be limited to sensory and hippocampal neurons but may be more generally applicable to other neurons. Further studies to reveal generalized principles underlying the regulation of neuroexcitability through SphK/ S1P signalling may provide a clue to novel therapeutic approaches in neuronal diseases. 7. Perspectives Recent studies on the role of SphK/S1P signalling in central nervous system indicate that this plays a pivotal role in neuron-specific functions such as neurotransmitter release from neurons as well as in more generalized functions including proliferation/survival and apoptosis of neurons and glia. Since synaptic transmission of excitatory and inhibitory neurotransmitters is vital for synaptogenesis and neuronal development [102–104], it needs to be clarified whether S1P has any role (s) in the release of inhibitory neurotransmitters such as GABA. Since glutamate release in the hippocampus has a central role in memory formation and learning, molecular mechanism underlying SphK/S1P signalling-based regulation of glutamate release may facilitate the understanding of the physiology of memory as well as pathology of excitotoxicity and epilepsy. These principles may also help give us novel therapeutic tools for epilepsy, and cognitive disorders including AD for manipulating S1P levels or S1P binding to its receptors. Acknowledgements Recent research in our laboratory is supported in part by a Grantin-Aid for COE Research and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture of Japan, the Bilateral Exchange Program between Japan Society for the Promotion of Science and Polish Academy of Sciences, and the Osaka Medical Research Foundation for Incurable Diseases.
References [1] Y.A. Hannun, C.R. Loomis, A.H.J. Merrill, R.M. Bell, J. Biol. Chem. 261 (1986) 12604–12609. [2] T. Okazaki, R.M. Bell, Y.A. Hannun, J. Biol. Chem. 264 (1989) 19076–19080. [3] M. Maceyka, S. Milstien, S. Spiegel, Circ. Res. 100 (2007) 7–9. [4] A.H.J. Merrill, J. Biol. Chem. 277 (2002) 25843–25846. [5] Y.A. Hannun, C. Luberto, Trends Cell Biol. 10 (2000) 73–80. [6] B.J. Pettus, C.E. Chalfant, Y.A. Hannun, Biochim. Biophys. Acta 1585 (2002) 114–125. [7] O. Cuvillier, Biochim. Biophys. Acta 1585 (2002) 153–162. [8] S. Spiegel, R. Kolesnick, Leukemia 16 (2002) 1596–1602. [9] M. Kohno, M. Momoi, M.L. Oo, J.H. Paik, Y.M. Lee, K. Venkataraman, Y. Ai, A.P. Ristimaki, H. Fyrst, H. Sano, D. Rosenberg, J.D. Saba, R.L. Proia, T. Hla, Mol. Cell. Biol. 26 (2006) 7211–7223. [10] J.K. Westwick, A.E. Bielawska, G. Dbaibos, Y.A. Hannun, D.A. Brenner, J. Biol. Chem. 207 (1995) 22689–22692. [11] A.M. Conway, N.J. Pyne, S. Pyne, Cell. Signal. 12 (2000) 737–743. [12] P.P. Van Veldhoven, Methods Enzymol. 311 (2000) 244–254. [13] S.M. Mandala, R. Thornton, I. Galve-Roperh, S. Poulton, C. Peterson, A. Olivera, J. Bergstrom, M.B. Kurtz, S. Spiegel, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 7859–7864. [14] D.N. Brindley, J. Cell Biochem. 92 (2004) 900–912. [15] H. Le Stunff, S. Milstien, S. Spiegel, J. Cell Biochem. 92 (2004) 882–899. [16] G. Labesse, D. Dougert, L. Assairi, A.M. Gilles, Trends Biochem. Sci. 27 (2002) 273–275. [17] H. Liu, D. Chakravarty, M. Maceyka, S. Milstien, S. Spiegel, Prog. Nucleic Acids Res. 71 (2002) 493–511. [18] A. Olivera, S. Spiegel, Prostaglandins Other Lipid Mediat. 64 (2001) 123–134. [19] T.A. Taha, Y.A. Hannun, L.M. Obeid, J. Biochem. Mol. Biol. 39 (2006) 113–131. [20] B.W. Wattenberg, S.M. Pitson, D.M. Raben, J. Lipid Res. 47 (2006) 1128–1139. [21] H. Liu, M. Sugiura, V.E. Nava, L.C. Edsall, K. Kono, S. Poulton, S. Milstien, T. Kohama, S. Spiegel, J. Biol. Chem. 275 (2000) 19513–19520. [22] A. Olivera, T. Kohama, L. Edsall, V. Nava, O. Cuvillier, S. Poulton, S. Spiegel, J. Cell Biol. 147 (1999) 545–557. [23] N. Igarashi, T. Okada, S. Hayashi, T. Fujita, S. Jahangeer, S. Nakamura, J. Biol. Chem. 278 (2003) 46832–46839.
[24] H. Liu, R.E. Toman, S.K. Goparaju, M. Maceyka, V.E. Nava, H. Sankala, S.G. Payne, M. Bektas, I. Ishii, J. Chun, S. Milstien, S. Spiegel, J. Biol. Chem. 278 (2003) 40330–40336. [25] T. Okada, G. Ding, H. Sonoda, T. Kajimoto, Y. Haga, A. Khosrowbeygi, S. Gao, N. Miwa, S. Jahangeer, S. Nakamura, J. Biol. Chem. 280 (2005) 36318–36325. [26] T.A. Taha, K. Kitatani, M. El-Alwani, J. Bielawski, Y.A. Hannun, L.M. Obeid, FASEB J. 20 (2006) 482–484. [27] Y. Inagaki, P.Y. Li, A. Wada, S. Mitsutake, Y. Igarashi, Biochem. Biophys. Res. Commun. 311 (2003) 168–173. [28] S.M. Pitson, R.J. D'andrea, L. Vandeleur, P.A. Moretti, P. Xia, J.R. Gamble, M.A. Vadas, B.W. Wattenberg, Biochem. J. 350 (2000) 429–441. [29] N. Urtz, A. Olivera, E. Bofill-Cardonna, R. Csonga, A. Billich, D. Mechtcheriakova, F. Bornancin, M. Woisetschlager, J. Rivera, T. Baumruker, Mol. Cell. Biol. 24 (2004) 8765–8777. [30] S.M. Pitson, P.A. Moretti, J.R. Zebol, H.E. Lynn, P. Xia, M.A. Vadas, B.W. Wattenberg, EMBO J. 22 (2003) 5491–5500. [31] N.C. Hait, A. Bellamy, S. Milstien, T. Kordula, S. Spiegel, J. Biol. Chem. 282 (2007) 12058–12065. [32] G. Ding, H. Sonoda, H. Yu, T. Kajimoto, S.K. Goparaju, S. Jahangeer, T. Okada, S. Nakamura, J. Biol. Chem. 282 (2007) 27493–27502. [33] R.V. Stahelin, J.H. Hwang, J.H. Kim, Z.Y. Park, K.R. Johnson, L.M. Obeid, W. Cho, J. Biol. Chem. 280 (2005) 43030–43038. [34] C. Delon, M. Manifava, E. Wood, D. Thompson, S. Krugmann, S. Pyne, N.T. Ktistakis, J. Biol. Chem. 279 (2004) 44763–44774. [35] A. Olivera, J. Rosenthal, S. Spiegel, J. Cell. Biochem. 60 (1996) 529–537. [36] P. Xia, L. Wang, P.A. Moretti, N. Albanese, F. Chai, S.M. Pitson, R.J. D'Andrea, J.R. Gamble, M.A. Vadas, J. Biol. Chem. 277 (2002) 7996–8003. [37] S. Hayashi, T. Okada, N. Igarashi, T. Fujita, S. Jahangeer, S. Nakamura, J. Biol. Chem. 277 (2002) 33319–33324. [38] A. Olivera, T. Kohama, Z. Tu, S. Milstien, S. Spiegel, J. Biol. Chem. 273 (1998) 12576–12583. [39] R. Alemany, B. Kleuser, L. Ruwisch, K. Danneberg, H. Lass, R. Hashemi, S. Spiegel, K.H. Jakobs, D. Meyer zu Heringdorf, FEBS Lett. 509 (2001) 239–244. [40] T.Y. Chin, H.M. Hwang, S.H. Chueh, Mol. Pharmacol. 61 (2002) 486–494. [41] C.J. van Koppen, D. Meyer zu Heringdorf, R. Alemany, K.H. Jakobs, Life Sci. 68 (2001) 2535–2540. [42] A. Olivera, L. Edsall, S. Poulton, A. Kazlauskas, S. Spiegel, FASEB J. 13 (1999) 1593–1600. [43] C.M. Sutherland, P.A. Moretti, N.M. Hewitt, C.J. Bagley, M.A. Vadas, S.M. Pitson, J. Biol. Chem. 281 (2006) 11693–11701. [44] Y. Yatomi, F. Ruan, S. Hakomori, Y. Igarashi, Blood 86 (1995) 193–202. [45] R. Pappu, S.R. Schwab, I. Cornelissen, J.P. Pereira, J.B. Regard, Y. Xu, E. Camerer, Y.W. Zheng, Y. Huang, J.G. Cyster, S.R. Coughlin, Science 316 (2007) 295–298. [46] K. Ito, Y. Anada, M. Tani, M. Ikeda, T. Sano, A. Kihara, Y. Igarashi, Biochem. Biophys. Res. Commun. 357 (2007) 212–217. [47] P. Hänel, P. Andréani, M.H. Gräler, FASEB J. 21 (2007) 1202–1209. [48] T.K. Ghosh, J. Bian, D.L. Gill, Science 248 (1990) 1653–1656. [49] T.K. Ghosh, J. Bian, D.L. Gill, J. Biol. Chem. 269 (1994) 22628–22635. [50] D. Meyer zu Heringdorf, K. Liliom, M. Schaefer, K. Danneberg, J.H. Jaggar, G. Tigyi, K.H. Jakobs, FEBS Lett. 554 (2003) 443–449. [51] A. Titievsky, I. Titievskaya, M. Pasternack, K. Kaila, K. Törnquist, J. Biol. Chem. 273 (1998) 242–247. [52] T. Blom, N. Bergelin, J.P. Slotte, K. Tornquist, Cell. Signal. 18 (2006) 1366–1375. [53] C. Mathes, A. Fleig, R. Penner, J. Biol. Chem. 273 (1998) 25020–25030. [54] K. Itagaki, C.J. Hauser, J. Biol. Chem. 278 (2003) 27540–27547. [55] S. Borges, S. Lindstrom, C. Walters, A. Warrier, M. Wilson, J. Physiol. 586 (2008) 605–626. [56] S. Spiegel, O. Cuvillier, L.C. Edsall, T. Kohama, R. Menzeleev, Z. Olah, A. Olivera, G. Pirianov, D.M. Thomas, Z. Tu, J.R. Van Brocklyn, F. Wang, Ann. N. Y. Acad. Sci. 845 (1998) 11–18. [57] R.E. Toman, S. Spiegel, Neurochem. Res. 27 (2002) 619–627. [58] K. Watterson, H. Sankala, S. Milstien, S. Spiegel, Prog. Lipid Res. 42 (2003) 344–357. [59] S.E. Alvarez, S. Milstien, S. Spiegel, Trends Endocrinol. Metab. 18 (2007) 300–307. [60] H. Rosen, E.J. Goetzl, Nat. Rev. Immunol. 5 (2005) 560–570. [61] S.R. Schwab, J.G. Cyster, Nat. Immunol. 8 (2007) 1295–1301. [62] P.S. Jolly, M. Bektas, A. Olivera, C. Gonzalez-Espinosa, R.L. Proia, J. Rivera, S. Milstien, S. Spiegel, J. Exp. Med. 199 (2004) 959–970. [63] P. Mitra, C.A. Oskeritzian, S.G. Payne, M.A. Beaven, S. Milstien, S. Spiegel, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 16394–16399. [64] Z. Li, C.D. Aizenman, H.T. Cline, Neuron 33 (2002) 741–750. [65] T. Nakamura, M. Komiya, K. Sone, E. Hirose, N. Gotoh, H. Morii, Y. Ohta, N. Mori, Mol. Cell. Biol. 22 (2002) 8721–8734. [66] S. Estrach, S. Schmidt, S. Diriong, A. Penna, A. Blangy, P. Fort, A. Debant, Curr. Biol. 12 (2002) 307–312. [67] C. Donati, P. Bruni, Biochim. Biophys. Acta 1758 (2006) 2037–2048. [68] J.R. Van Brocklyn, Z. Tu, L.C. Edsall, R.R. Schmidt, S. Spiegel, J. Biol. Chem. 274 (1999) 4626–4632. [69] A.J. MacLennan, B.K. Devlin, L. Marks, A.A. Gaskin, K.L. Neitzel, N. Lee, Dev. Neurosci. 22 (2000) 283–295. [70] R.E. Toman, S.G. Payne, K.R. Watterson, M. Maceyka, N.H. Lee, S. Milstien, J.W. Bigbee, S. Spiegel, J. Cell Biol. 166 (2004) 381–392. [71] M. Murakami, M. Ichihara, S. Sobue, R. Kikuchi, H. Ito, A. Kimura, T. Iwasaki, A. Takagi, T. Kojima, M. Takahashi, M. Suzuki, Y. Banno, Y. Nozawa, T. Murate, J. Neurochem. 102 (2007) 1585–1594. [72] L. Strochlic, A. Dwivedy, F.P. van Horck, J. Falk, C.E. Holt, Development 135 (2008) 333–342.
T. Okada et al. / Cellular Signalling 21 (2009) 7–13 [73] C. McGiffert, J.J. Contos, B. Friedman, J. Chun, FEBS Lett. 531 (2002) 103–108. [74] Y. Liu, R. Wada, T. Yamashita, Y. Mi, C.X. Deng, J.P. Hobson, H.M. Rosenfeldt, V.E. Nava, S.S. Chae, M.J. Lee, C.H. Liu, T. Hla, S. Spiegel, R.L. Proia, J. Clin. Invest. 106 (2000) 951–961. [75] J. Harada, M. Foley, M.A. Moskowitz, C. Waeber, J. Neurochem. 88 (2004) 1026–1039. [76] K. Mizugishi, T. Yamashita, A. Olivera, G.F. Miller, S. Spiegel, R.L. Proia, Mol. Cell. Biol. 25 (2005) 11113–11121. [77] J. Mitoma, M. Ito, S. Furuya, Y. Hirabayashi, J. Neurosci. Res. 51 (1998) 712–722. [78] S.E. Ping, G.L. Barrett, J. Neurosci. Res. 54 (1998) 206–213. [79] K. Shinpo, S. Kikuchi, F. Moriwaka, K. Tashiro, Brain Res. 819 (1999) 170–173. [80] A.J. MacLennan, S.J. Benner, A. Andringa, A.H. Chaves, J.L. Rosing, R. Vesey, A.M. Karpman, S.A. Cronier, N. Lee, L.C. Erway, M.L. Miller, Hear. Res. 220 (2006) 38–48. [81] M. Kono, I.A. Belyantseva, A. Skoura, G.I. Frolenkov, M.F. Starost, J.L. Dreier, D. Lidington, S.S. Bolz, T.B. Friedman, T. Hla, R.L. Proia, J. Biol. Chem. 282 (2007) 10690–10696. [82] D.R. Herr, N. Grillet, M. Schwander, R. Rivera, U. Müller, J. Chun, J. Neurosci. 27 (2007) 1474–1478. [83] C.L. Chik, B. Li, T. Negishi, E. Karpinski, A.K. Ho, Endocrinology 140 (1999) 5682–5690. [84] A.J. MacLennan, P.R. Carney, W.J. Zhu, A.H. Chaves, J. Garcia, J.R. Grimes, K.J. Anderson, S.N. Roper, N. Lee, Eur. J. Neurosci. 14 (2001) 203–209. [85] T. Numakawa, H. Nakayama, S. Suzuki, T. Kubo, F. Nara, Y. Numakawa, D. Yokomaku, T. Araki, T. Ishimoto, A. Ogura, T. Taguchi, J. Biol. Chem. 278 (2003) 41259–41269. [86] Y.H. Zhang, G.D. Nicol, Neurosci. Lett. 366 (2004) 187–192. [87] Y.H. Zhang, M.R. Vasko, G.D. Nicol, J. Physiol. (2006). [88] T. Kajimoto, T. Okada, H. Yu, S. Goparaju, S. Jahangeer, S. Nakamura, Mol. Cell. Biol. 27 (2007) 3429–3440. [89] T. Kanno et al. Manuscript in preparation.
13
[90] H.A. Cameron, R.D. McKay, J. Comp. Neurol. 435 (2001) 406–417. [91] T.J. Shors, G. Miesegaes, A. Beylin, M. Zhao, T. Rydel, E. Gould, Nature 410 (2001) 372–376. [92] T. Ariga, W.D. Jarvis, R.K. Yu, J. Lipid Res. 39 (1998) 1–16. [93] C.L. Masters, G. Multhaup, G. Simms, J. Pottgiesser, R.N. Martins, K. Beyreuther, EMBO J. 4 (1985) 2757–2763. [94] B.A. Yankner, L.R. Dawes, S. Fisher, L. Villa-Komaroff, M.L. Oster-Granite, R.L. Neve, Science 245 (1989) 417–420. [95] T. Thomas, G. Thomas, C. McLendon, T. Sutton, M. Mullan, Nature 380 (1996) 168–171. [96] A. Jana, K. Pahan, J. Biol. Chem. 279 (2004) 51451–51459. [97] C. Zeng, J.T. Lee, H. Chen, S. Chen, C.Y. Hsu, J. Xu, J. Neurochem. 94 (2005) 703–712. [98] A.V. Alessenko, A.E. Bugrova, L.B. Dudnik, Biochem. Soc. Trans. 32 (2004) 144–146. [99] C. Garcia-Ruiz, A. Colell, M. Mari, A. Morales, J.C. Fernandez-Checa, J. Biol. Chem. 272 (1997) 11369–11377. [100] M. Maceyka, S. Milstien, S. Spiegel, Circ. Res. 100 (2007) 7–9. [101] D. Pchejetski, O. Kunduzova, A. Dayon, D. Calise, M.H. Seguelas, N. Leducq, I. Seif, A. Parini, O. Cuvillier, Circ. Res. 100 (2007) 41–49. [102] C. Ikonomidou, F. Bosch, M. Miksa, P. Bittigau, J. Vockler, K. Dikranian, T.L. Tenkova, V. Stefovska, L. Turski, J.W. Olney, Science 283 (1999) 70–74. [103] H. van Praag, A.F. Schinder, B.R. Christie, N. Toni, T.D. Palmer, F.H. Gage, Nature 415 (2002) 1030–1034. [104] M. Verhage, A.S. Maia, J.J. Plomp, A.B. Brussaard, J.H. Heeroma, H. Vermeer, R.F. Toonen, R.E. Hammer, T.K. van den Berg, M. Missler, H.J. Geuze, T.C. Sudhof, Science 287 (2000) 864–869.
Contents lists available at ScienceDirect
Cellular Signalling j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c e l l s i g
Review
Sphingosine kinase/sphingosine 1-phosphate signalling in central nervous system Taro Okada, Taketoshi Kajimoto, Saleem Jahangeer, Shun-ichi Nakamura ⁎ Division of Biochemistry, Department of Biochemistry/Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
a r t i c l e
i n f o
Article history: Received 31 March 2008 Received in revised form 4 July 2008 Accepted 17 July 2008 Available online 22 July 2008 Keywords: Sphingosine 1-phosphate Sphingosine kinase Neurotransmitter Alzheimer's disease Neuron Central nervous system Apoptosis
a b s t r a c t Sphingolipids were once regarded as inert structural components of cell membranes. Now these metabolites are generally believed to be important bioactive molecules that control a wide repertoire of cellular processes such as proliferation and survival of cells. Along with these ubiquitous cell functions observed in many peripheral tissues sphingolipid metabolites, especially sphingosine 1-phosphate, exert important neuronspecific functions such as regulation of neurotransmitter release. This review summarizes physiological and pathological roles of sphingolipid metabolites emphasizing the role of sphingosine 1-phosphate in the central nervous system. © 2008 Elsevier Inc. All rights reserved.
Contents 1. 2. 3. 4. 5.
6. 7.
Introduction . . . . . . . . . . . . . . . Sphingolipid metabolism . . . . . . . . . SphK . . . . . . . . . . . . . . . . . . Mode of actions of S1P . . . . . . . . . . SphK/S1P signalling in CNS . . . . . . . . 5.1. Neurite extension and retraction . . 5.2. Proliferation, survival and apoptosis 5.3. Neurotransmitter release . . . . . Sphingolipids and neuronal disease . . . . Perspectives . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
7 8 8 9 10 10 10 10 11 12
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
1. Introduction Sphingolipids have long been regarded as structural components of cell membranes. Increased attention has been paid to sphingolipid metabolism following the discovery that protein kinase C could be inhibited by the sphingolipid metabolite sphingosine [1]. The physiological roles of ceramide as intracellular biomodulator
Abbreviations: S1P, Sphingosine 1-phosphate; SphK, Sphingosine kinase; PMA, Phorbol 12-myristate 13-acetate; TNFα, Tumor necrosis factor α; EGF, Epidermal growth factor; ERK, Extracellular signal-regulated kinase; S1P1–5, S1P receptor type 1–5; PA, Phosphatidic acid; PLD, Phospholipase D; AD, Alzheimer's disease; Aβ, amyloid β-peptide. ⁎ Corresponding author. Tel.: +81 78 382 5420; fax: +81 78 382 5439. E-mail address: [email protected] (S. Nakamura). 0898-6568/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2008.07.011
were then highlighted by the observation that sphingomyelin hydrolysis and ceramide generation could be triggered by diverse stimuli in a wide variety of cell types [2]. It has now become clear that once ceramide is generated from sphingomyelin, it can be converted into a number of other bioactive sphingolipids, including ceramide 1-phosphate, sphingosine and sphingosine 1-phosphate (S1P). Ceramide regulates stress responses by inducing growth arrest or apoptosis, whereas S1P promotes cell proliferation and cell survival and the dynamic balance between these two signalling bioactive lipids, termed sphingolipid rheostat, determines cell's fate either to survive or to die [3]. The role of sphingolipid metabolites in neuronal tissues was studied mainly based on an analogy of the results obtained in nonneuronal systems. Recent observations, however, clearly show that
8
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
sphingomyelin metabolite S1P additionally exerts its neuron-specific role, e.g., regulation of neurotransmitter release. This review summarizes the neuronal functions of sphingolipid metabolites with emphasis on S1P and sphingosine kinase (SphK), a key enzyme for the production of S1P, and discusses its role in neuronal disorders. 2. Sphingolipid metabolism Sphingolipids are a class of complex lipids containing an amidelinked fatty acid and a long-chain (sphingoid) base that are important structural components of cell membranes. Different combinations of sphingoid bases, fatty acids and head group moieties lead to a large number of sphingolipids and glycosphingolipids. De novo synthesis of sphingolipids is initiated by the condensation of serine and palmitate through a complex series of synthetic pathways [4]. Cell signalling through sphingolipids starts from the degradation of sphingomyelin by sphingomyelinases under various cellular environments such as exposure to inflammatory cytokine stimulation and stress [5]. Once ceramide is generated it can be converted into a number of bioactive sphingolipids, including ceramide 1-phosphate, sphingosine, and S1P [6–8]. Sphingosine and ceramide are generally considered to inhibit cell proliferation. For example, treatment of RIE cells with sphingosine has been shown to suppress retinoblastoma (Rb) protein phosphorylation and Cdk4 protein expression levels [9] thus suppressing cell proliferation. Similarly, ceramide is reported to activate the stress-activated protein kinases (SAPKs, also known as Jun nuclear kinases or JNKs) [10]. However ceramide can also activate a novel signal transduction/cell survival pathway involving tyrosine kinases (e.g. PDGF receptor kinase), phosphoinositide 3-kinase (PI3K) and PKC to promote c-Raf dependent activation of the p42/p44 MAPK cascade [11]. This ability of ceramide to exploit PI3K-dependent signalling suggests that ceramide might be antiapoptotic at least in some cells [11]. Cellular levels of S1P are regulated by the concerted action of the enzymes responsible for its formation and degradation (Fig. 1). S1P is biosynthesized through the phosphorylation of sphingosine via SphK and its metabolic fate includes the irreversible cleavage to transhexadecenal and ethanolamine phosphate by a pyridoxal phosphate-
dependent lyase [12], or the hydrolytic removal of the phosphomonoester group by S1P phosphatase or lipid-phosphate phosphatases [13–15]. 3. SphK SphKs are members of lipid kinases and are evolutionarily well conserved, holding common sequences in protozoa, yeast, plants and mammals [16,17]. Two mammalian isoforms of SphK, SphK1 and SphK2 with molecular masses of 43 and 65 kDa, respectively, have been identified through molecular cloning [18–20]. Almost all of the SphK1 sequence aligns with a region of the SphK2 sequence, with an 80% similarity [21]. SphK2, however, also possesses two additional divergent sequences at its N terminus and in the middle of its sequence, suggesting distinct biological functions. Indeed, it has been shown that exogenously expressed SphK1 causes cell proliferation [22] whereas SphK2 overexpression results in inhibition of proliferation [23] or in apoptosis [24,25]. In addition, down-regulation of SphK1 by siRNA treatment has also been shown to activate proapoptotic events in the cells such as translocation of Bax/Bcl-2 to mitochondria and its oligomerization, mitochondrial membrane permeabilization (MMP), release of cytochrome c and activation of executioner caspase 7 [26]. Correspondingly, the two isoforms show quite distinct patterns of subcellular distribution. SphK1 is distributed exclusively in the cytoplasm [22] due to extensive export from the nucleus by its nuclear export signal activity [27]. On the other hand, SphK2 possesses a nuclear import signal as well as nuclear export signals and shuttles between the nucleus and cytoplasm depending on cellular conditions, i.e., it enters the nucleus under the conditions of high cell density [23] or stress such as serum removal [25] and stops proliferation or induces apoptosis. There are several possible mechanisms underlying SphK2-induced apoptosis, e.g., S1P produced within the nucleus catalyzed by SphK2 might induce apoptosis through as yet unidentified intranuclear mechanisms or increased ceramide level in the cytoplasm as a result of SphK2 sequestration in the nucleus may induce apoptosis. There is also a report that SphK2induced apoptosis through a motif similar to that present in Bcl-2-
Fig. 1. Pathways of sphingolipid metabolism. The pathway of sphingolipid metabolism is depicted emphasizing bioactive lipid mediators ceramide and S1P. Although intracellular actions of S1P are poorly defined, the mechanism underlying S1P receptor-mediated actions is becoming clearer.
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
homology domain 3 (BH3)-only proteins, a pro-apoptotic subgroup of the Bcl-2 family, although mutation of the conserved leucines present in BH3 domains in SphK2 caused only partial reduction of SphK2induced apoptosis [24]. SphKs exhibit substantial basal activity since recombinant enzymes expressed in Escherichia coli thus containing no mammalian modifications exhibit enzyme activity comparable to that prepared from mammalian expression systems [28]. Therefore, spatio/temporal changes in compartmentalization of the enzymes may play a determinant role in the regulation of SphK/S1P-mediated signalling. SphKs do not have obvious membrane-anchoring sequences and usually behave as soluble enzymes under basal conditions, however upon stimulation SphKs are known to undergo activation and translocation by mechanisms involving protein phosphorylation, protein–lipid binding, protein–protein interaction, and calcium/ calmodulin (see e.g., [29]). Several agonists such as phorbol 12-myristate 13-acetate (PMA) or TNFα have been shown to cause an extracellular signal-regulated kinase (ERK)-dependent phosphorylation of SphK1 at Ser-225, which is important for subsequent translocation of the enzyme to the plasma membrane [30]. Similarly, PMA or EGF induces an ERK-dependent phosphorylation of SphK2 at Ser-351 and Thr-578 that is important for EGF-stimulated migration of MDA-MB-453 cells [31]. Another line of evidence suggests that PMA treatment results in a protein kinase D-mediated phosphoryaltion of SphK2 at Ser-419 and Ser-421 in the nuclear export signal sequence and subsequent export of the enzyme from the nucleus [32]. In addition to the regulation by phosphorylation membrane recruitment of SphK1 may also involve protein–lipid interactions. The conserved residues Thr-54 and Asn-89 in the putative membranebinding surface of SphK1 are essential for selective binding of the enzyme to phosphatidylserine and membrane targeting [33]. The same study also suggested that phosphorylation of SphK1 at Ser-225 enhances the membrane affinity and plasma membrane selectivity of SphK1, presumably by modulating the interaction of Thr-54 and Asn89 with the membrane. Besides phosphatidylserine, phosphatidic acid (PA) produced by phospholipase D (PLD) has been proposed to be a factor to affect SphK cellular distribution. The membranes enriched in PA may be physiologically important sites of S1P production [34]. It has been reported that SphK1 interacts directly with PA and this high affinity interaction is responsible for the translocation/localization of SphK1 to the Golgi apparatus and early endosomes in cells where PLD1 has been induced. The colocalization of SphK1 and PLD1, under conditions of PLD1 activation has led to the idea that SphK1 is a downstream effector of PA [34]. In addition to binding, PA has been proposed to enhance the enzyme activity of SphK [28,35]. Protein–protein interaction also plays roles in recruiting SphKs to specialized compartments in the cells. The activation of SphK1 at the membrane by TNFα requires its interaction with the adapter molecule TRAF2 [36]. Interestingly, while protein–protein interaction is required for SphK1 activation by TNFα, it is not necessary for the activation of the enzyme by PMA, suggesting that although both agonists induce translocation of SphK1 to the membranes by an ERK-dependent phosphorylation of Ser-225, the activation of SphK1 at the membrane occurs by distinct mechanisms. The interaction of SphK1 with another adopter molecule, RPK118, is important for the localization of the enzyme at early endosomes [37]. RPK118 contains a PX domain that specifically binds to phosphatidylinositol 3-phosphate, a unique lipid which is enriched in early endosomes, thus recruiting SphK1 to early endosomes and presumably regulating vesicular trafficking. In addition, it has been reported that SphK1 directly interacts with the src family tyrosine kinase Lyn (in vivo as well as in vitro) and this leads to the recruitment of SphK to the high affinity FcɛRI during immunoglobulin E (IgE) dependent mast cell activation, an interaction that leads to the enhancement of lipid and tyrosine kinase activity in sphingolipidenriched rafts [29].
9
Calcium also regulates SphK activity as well as its subcellular localization. SphK1 possesses putative calcium/calmodulin binding motifs, and the enzyme binds to a calmodulin affinity column in the presence of calcium [38]. Involvement of calcium in the regulation of SphK has been suggested by several studies. Membrane depolarization causes SphK activation by a mechanism sensitive to the Ca2+ channel blocker verapamil, suggesting that calcium influx from intracellular stores by the voltage-gated Ca2+ channel mediates SphK activation [39]. Calcium mobilization from intracellular stores by the Ca2+-ATPase inhibitor thapsigargin activates SphK [40]. Attenuation of calcium levels by the calcium chelator BAPTA/AM inhibits S1P formation in response to the activation of muscarinic, formyl peptide, and P2Y2 purinergic receptors [41]. The importance of phospholipase C in producing transient calcium signals to activate SphK was emphasized by Olivera et al. where a mutation in the phospholipase C binding domain of the platelet-derived growth factor receptor abrogates SphK activation [42]. More recently it has been shown that an SphK1 mutant, which lacks the ability of calmodulin binding, failed to undergo agonist-dependent translocation to plasma membrane [43]. Although several lines of evidence indicate the involvement of calcium signal in the activation of SphK, calcium/calmodulin has no effect on the enzyme activity in vitro [28], suggesting the participation of other molecule(s) in the calcium-dependent SphK activation. 4. Mode of actions of S1P S1P is found in high concentrations in human serum (0.5 µM) [44]. Recently, it has been reported that erythrocytes might be the major contributors of S1P in serum [45–47]. S1P exerts several effects on cells including proliferation, survival, regulation of cell motility, and cytoskeletal reorganization. Most of the effects are mediated by the interaction of S1P with the cell surface S1P receptors as well as the intracellular action of S1P as a second messenger (Fig. 1). Although the mechanism of intracellular action of S1P has not been clearly understood, it is believed that S1P is involved in calcium homeostasis in various cells. S1P induces Ca2+ release from microsomal membrane vesicles enriched in rough endoplasmic reticulum [48,49]. Photolysis of intracellular caged S1P causes calcium mobilization independently of G-protein-coupled receptors in HEK-293, SKNMC and HepG2 cells [50]. On the other hand, SphK pathway is also involved in the regulation of calcium channels. Sphingosine inhibits voltage-operated calcium channel in pituitary GH4C1 cells [51] and SphK regulates the function of the channel by removal of the substrate sphingosine [52]. Sphingosine also inhibits calcium releaseactivated calcium current (ICRAC) through direct block of ICRAC channels [53]. Furthermore Itagaki and Hauser proposed that S1P is a calcium influx factor linking calcium store depletion to downstream store-operated calcium entry (SOCE) [54]. Involvement of S1P in the SOCE pathway has also been reported in chick retinal neurons [55]. The binding of S1P to the S1P receptors activates different signalling pathways involving heterotrimeric G proteins which, in turn, control adenylate cyclase, phospholipases C an D, phosphoinositide 3-kinase, c-Jun N-terminal kinase, ERK, p38, small GTPases such as Rac and Rho and probably non-receptor protein-tyrosine kinases and tyrosine phosphatases [56–58]. Importantly, intracellularly generated S1P resulting from activation of SphK can be exported out of cells and functions as a ligand for S1P receptors [59,60] to regulate a wide variety of cellular responses. For example, S1P receptor type 1 (S1P1) is needed in T and B cells for their egress from the thymus and secondary lymphoid organs [61]. In mast cells cross-linking of FcγRI has been shown to activate SphK and increase S1P secretion, leading to autocrine/paracrine activation of S1P1, which is important for their migration toward antigen, and S1P2, which regulates their degranulation [62]. It has recently been demonstrated that intracellular S1P produced upon FcγRI crosslinking is exported out of mast cells at least in part by an ATP binding
10
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
cassette transporter, ABCC1, independently of their degranulation [63], suggesting an autocrine/paracrine action of S1P. In addition, S1P receptor activation of neurons has been shown to play an important role in the potentiation of neurotransmitter release (see below). 5. SphK/S1P signalling in CNS 5.1. Neurite extension and retraction Neurite extension and retraction are important processes in the establishment of neuronal networks during development and are largely regulated by the organization of the actin cytoskeleton controlled by the balance between the opposing actions of the small GTPases, Rho and Rac [64]. Although Rho induces collapse of growth cones and inhibition of neurite outgrowth [65], Rac is required for neurite outgrowth [66]. Of interest, in diverse cell types, S1P receptors differentially regulate Rac and Rho. Generally, binding of S1P to S1P1 causes Rac activation, whereas S1P2 results in Rho activation (reviewed in [67]). For example, addition of S1P to PC12 cells transiently expressing S1P2 caused cell rounding [68] and similarly, downregulation of S1P2 by antisense oligonucleotides has been shown to enhance neurite extension and prevent S1P-induced rounding in PC12 cells [69]. Moreover, treatment of PC12 cells with NGF causes SphK1 activation and subsequent translocation from the cytosol to the plasma membrane to generate S1P in a spatially and temporally restricted manner [70]. This S1P binds to and activates S1P1 on the cell surface, leading to the activation of signalling pathways important for neurite extension. Similarly, glial cell line-derived neurotrophic factor/RET signalling transactivates SphK/S1P signalling and induces neurite extension through S1P1 receptor [71]. Molecular mechanisms underlying neurotropic factor-induced SphK activation remain to be clarified. Furthermore, SphK/S1P signalling system may be involved in axon guidance in the Xenopus visual system. Strochlic et al. showed that S1P induces rapid collapse and repulsive turning of Xenopus retinal neuron through S1P5 and that gain or loss of SphK–S1P pathway in vivo causes errors in axon navigation [72]. 5.2. Proliferation, survival and apoptosis Neurogenesis in central nervous system is essential for creating neuronal networks during embryonic development as well as in some areas of adult brain such as hippocampal formation. By analogy to roles of S1P observed mostly in non-neuronal cells it has been considered that S1P plays roles in neuronal proliferation. To support this idea, expression of S1P1 receptor is prominent both in cerebral cortical proliferative zone and in ventricular areas of the mesencephalon and coincides with the period of neurogenesis [73]. In addition, embryonic S1P1-null mice die before most neurons are generated [74]. In an in vitro study S1P has been shown to stimulate neural stem/progenitor cell proliferation through a Gi-coupled receptor and promotes their differentiation into neurons and astrocytes in an S1P receptor-mediated fashion [75]. Furthermore, physiological importance of SphK/S1P signalling in neurogenesis has been demonstrated by using SphK1/SphK2 double-knockout mice as well as S1P1 receptor-null mice showing severely disturbed neurogenesis resulting in embryonic lethality [76]. While neuronal survival is essential for the maintenance of the neuronal circuits that ensure the proper functioning of the postmitotic neurons in the adult, it is also known that apoptosis is a physiological event in the development of the mammalian nervous system. Loss of neurons is an important adaptive mechanism for establishing functional neuronal populations and to guarantee the elimination of neurons that contact inappropriate targets. Thus neuronal survival and apoptosis are reciprocal and physiologically important processes for the maintenance and remodeling of postmitotic neuronal functions. For the regulation of neuronal survival
and apoptosis sphingolipids especially ceramide and S1P play an important role. Generally, cellular effects of ceramide and S1P are different depending on cell types, concentrations of these lipids, and developmental stages. In hippocampal neurons at immature stages exogenous ceramide promotes survival at low concentrations although it triggers cell death at concentrations higher than 5 µM [77]. Interestingly, mature hippocampal neurons undergo nonnecrotic cell death at the same low concentrations of ceramide. Ceramide provided to sensory neurons protects from NGF withdrawal-induced apoptosis, however, the actual lipid mediator seems to be its metabolites since in the presence of the ceramidase inhibitor N-oleoyl-ethanolamine, ceramide induces apoptosis [78]. Similarly, in mesencephalic neurons inhibition of the conversion of ceramide into S1P by dimethylsphingosine blocks the protection against excitotoxicity [79]. More recently importance of S1P signalling in cell survival has been shown using S1P receptor-null mice. S1P2 receptor-knockout mice display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness suggesting that S1P2 receptor-mediated signal is essential for survival of hair cells and proper functioning of the auditory and vestibular systems [80–82]. 5.3. Neurotransmitter release Sphingolipid metabolites such as ceramide, sphingosine and S1P have been proposed to be involved in the regulation of neurotransmitter release. For example, sphingosine inhibits voltage-activated calcium channels in pituitary cells [51]. Ceramide also inhibits L-type Ca2+ channels in rat pinealocytes [83]. However it is not clear whether these effects are mediated by the lipid or the further metabolites. The possible involvement of S1P in neurotransmitter release was further suggested by several lines of evidence. Alemany et al. have shown that depolarization induces rapid and transient formation of intracellular S1P in PC12 cells and have postulated that the rise in S1P concentration during depolarization may contribute to depolarization-induced noradrenaline release and Ca2+ increase in these cells [39]. The contribution of S1P in neuronal excitability was strongly suggested by the observation that S1P2-null mice have spontaneous seizures and display significant increases in excitatory postsynaptic currents [84] although precise mechanism underlying the involvement of the S1P receptor in neuroexcitability is unknown. Furthermore, in developing cerebellar neurons NGF induces glutamate release and release of Ca2+ from ryanodine receptor via its p75 neurotrophin receptor where ceramide generation by sphingomyelinase activation seems to be necessary since scyphostatin, a sphingomyelinase inhibitor, blocks the NGF-dependent Ca2+ increase and glutamate release [85]. Similarly, NGF can increase the excitability of nociceptive sensory neurons through activation of the p75 receptor and its consequent liberation of ceramide from sphingomyelin [86] and the same group has subsequently shown that intracellular S1P derived from ceramide acts as an internal second messenger to suppress the outward K+ currents (IK), which enhances the excitability of the sensory neurons; however, the effector system whereby S1P modulates IK remains undetermined [87]. S1P receptor-mediated regulation of neurotransmitter release was further demonstrated in hippocampal neurons. S1P is involved in glutamate secretion from hippocampal neurons through an autocrine/paracrine action: S1P at a nanomolar concentration by itself elicits glutamate secretion from hippocampal neurons even when the Na+-channel is blocked by tetrodotoxin, while S1P at a picomolar level potentiates depolarization-evoked glutamate secretion. Importantly, depolarization causes the activation of S1P1 on the presynapses of hippocampal neurons, which is inhibited by the knockdown of SphK1 [88] (Fig. 2) although mechanisms underlying S1P-induced neurotransmitter release remain to be clarified. Furthermore SphK inhibitors such as dimethylsphingosine and 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
11
Fig. 2. Current model of mechanism underlying neurotransmitter release from presynaptic nerve terminal via SphK/S1P signalling pathway. During depolarization SphK1 is activated by an unidentified mechanism and is translocated from the cytosol to membranes at puncta or boutons of presynaptic neurons and produces S1P in close proximity to where S1P1 receptor is present. S1P may be transported via ATP binding cassette transporter, ABCC1 and activate S1P1, which may facilitate the enhancement or induction of neurotransmitter release depending on S1P concentrations produced [74].
thiazole significantly decreased the rate of spontaneous AMPAminiature excitatory postsynaptic currents for CA3 pyramidal neurons in hippocampal slices prepared from adult rats [89], indicating that S1Pelicited spontaneous AMPA secretion may be relevant in adult rat hippocampal functions. The notion that SphK/S1P signalling plays an important role in the regulation of neurotransmitter release is important for the understanding of molecular mechanisms underlying synaptic transmission of signals as well as synaptogenesis. Consistent with the observation that spontaneous AMPA-miniature excitatory postsynaptic currents were observed in CA3 but not in CA1 pyramidal neurons in hippocampal slices in adult rats, immunohistochemical analysis showed that SphK1 was enriched in mossy fibers from granular cells in the dentate gyrus, projecting towards CA3 pyramidal neurons in the hippocampus, but the enzyme was undetectable in Schaffer collaterals from CA3 pyramidal neurons projecting towards CA1 pyramidal neurons [89]. For the hippocampus of the adult rat thousands of new granule cells are generated per day [90]. The ongoing neurogenesis in the adult has recently been implicated in the formation of hippocampus-dependent memories such as tracing memory conditions [91]. The mechanisms of synaptogenesis of newly produced neurons with preexisting neuronal networks during adult neurogenesis as well as synaptogenesis which occurred in the developmental stages are largely unexplored yet. The observation that SphK1/SphK2 double-knockout mice as well as S1P1 receptornull mice show severe defects in neuronal development including neural tube closure shows pivotal role of SphK/S1P signalling system in the central nervous system development [76]. Recent observations support the notion that S1P is one of the important determinants for triggering spontaneous secretion of neurotransmitters such as glutamate [88,89]. Further studies on the role of S1P in the synaptogenesis in hippocampal neurons may facilitate the understanding of memory formation and learning. It is also important to clarify whether this concept is applicable to other neurotransmitter systems in various brain regions.
6. Sphingolipids and neuronal disease Although apoptosis along with proliferation/survival are essential for neuronal tissue maintenance and remodeling, inappropriate activation of apoptosis may contribute to neurodegenerative disorders such as Alzheimer's disease (AD) [92]. The progressive impairment of short-term memory and emotional disturbances that characterizes AD result from the dysfunction and death of neurons in the hippocampus and associated regions of the cerebral cortex and limbic system. Although the pathogenesis of AD is not completely understood, accumulation of the amyloid β-peptide (Aβ) is postulated to cause neuronal degeneration in AD brains [93–95]. In addition, studies in human neurons [96], oligodendrocytes [97] and brain sections [98] provide direct evidence that the Aβ peptide that accumulates in AD causes neutral sphingomyelinase activation and subsequent ceramide accumulation. Since it is becoming apparent that oxidative stress and ceramide generation are intimately connected in cell death signalling [99–101], oxidative stress and excessive production and accumulation of Aβ may cause neuronal cell death through abnormal sphingolipid metabolism. In addition to neurodegenerative disorders sphingolipid metabolites such as S1P may have profound effects on neuronal diseases related to increased excitability. To support this possibility S1P seems to have a role in the modulation of neuronal excitability since S1P2 receptor-null mice have spontaneous seizures and display significant increase in excitatory postsynaptic currents. These mice displayed no apparent anatomical or physiological defects, however, they showed spontaneous and sporadic seizures between 3 and 7 weeks of age. Although precise mechanism underlying increased neuronal excitability in these mice remains unknown, this is suggestive of potential causal relationship between S1P and neuronal excitability. Recent observations that NGF-induced production of S1P causes neuronal excitability in sensory neurons [87] and that S1P produced under basal conditions or during depolarization causes spontaneous or potentiation of glutamate release from hippocampal neurons, respectively [88] indicate that sphingolipid metabolites
12
T. Okada et al. / Cellular Signalling 21 (2009) 7–13
play a pivotal role in neuron-specific function such as neurotransmitter secretion in the central nervous system in addition to other roles such as proliferation, survival, and apoptosis seen in peripheral tissues. The ability of S1P to cause neuronal excitability may not be limited to sensory and hippocampal neurons but may be more generally applicable to other neurons. Further studies to reveal generalized principles underlying the regulation of neuroexcitability through SphK/ S1P signalling may provide a clue to novel therapeutic approaches in neuronal diseases. 7. Perspectives Recent studies on the role of SphK/S1P signalling in central nervous system indicate that this plays a pivotal role in neuron-specific functions such as neurotransmitter release from neurons as well as in more generalized functions including proliferation/survival and apoptosis of neurons and glia. Since synaptic transmission of excitatory and inhibitory neurotransmitters is vital for synaptogenesis and neuronal development [102–104], it needs to be clarified whether S1P has any role (s) in the release of inhibitory neurotransmitters such as GABA. Since glutamate release in the hippocampus has a central role in memory formation and learning, molecular mechanism underlying SphK/S1P signalling-based regulation of glutamate release may facilitate the understanding of the physiology of memory as well as pathology of excitotoxicity and epilepsy. These principles may also help give us novel therapeutic tools for epilepsy, and cognitive disorders including AD for manipulating S1P levels or S1P binding to its receptors. Acknowledgements Recent research in our laboratory is supported in part by a Grantin-Aid for COE Research and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture of Japan, the Bilateral Exchange Program between Japan Society for the Promotion of Science and Polish Academy of Sciences, and the Osaka Medical Research Foundation for Incurable Diseases.
References [1] Y.A. Hannun, C.R. Loomis, A.H.J. Merrill, R.M. Bell, J. Biol. Chem. 261 (1986) 12604–12609. [2] T. Okazaki, R.M. Bell, Y.A. Hannun, J. Biol. Chem. 264 (1989) 19076–19080. [3] M. Maceyka, S. Milstien, S. Spiegel, Circ. Res. 100 (2007) 7–9. [4] A.H.J. Merrill, J. Biol. Chem. 277 (2002) 25843–25846. [5] Y.A. Hannun, C. Luberto, Trends Cell Biol. 10 (2000) 73–80. [6] B.J. Pettus, C.E. Chalfant, Y.A. Hannun, Biochim. Biophys. Acta 1585 (2002) 114–125. [7] O. Cuvillier, Biochim. Biophys. Acta 1585 (2002) 153–162. [8] S. Spiegel, R. Kolesnick, Leukemia 16 (2002) 1596–1602. [9] M. Kohno, M. Momoi, M.L. Oo, J.H. Paik, Y.M. Lee, K. Venkataraman, Y. Ai, A.P. Ristimaki, H. Fyrst, H. Sano, D. Rosenberg, J.D. Saba, R.L. Proia, T. Hla, Mol. Cell. Biol. 26 (2006) 7211–7223. [10] J.K. Westwick, A.E. Bielawska, G. Dbaibos, Y.A. Hannun, D.A. Brenner, J. Biol. Chem. 207 (1995) 22689–22692. [11] A.M. Conway, N.J. Pyne, S. Pyne, Cell. Signal. 12 (2000) 737–743. [12] P.P. Van Veldhoven, Methods Enzymol. 311 (2000) 244–254. [13] S.M. Mandala, R. Thornton, I. Galve-Roperh, S. Poulton, C. Peterson, A. Olivera, J. Bergstrom, M.B. Kurtz, S. Spiegel, Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 7859–7864. [14] D.N. Brindley, J. Cell Biochem. 92 (2004) 900–912. [15] H. Le Stunff, S. Milstien, S. Spiegel, J. Cell Biochem. 92 (2004) 882–899. [16] G. Labesse, D. Dougert, L. Assairi, A.M. Gilles, Trends Biochem. Sci. 27 (2002) 273–275. [17] H. Liu, D. Chakravarty, M. Maceyka, S. Milstien, S. Spiegel, Prog. Nucleic Acids Res. 71 (2002) 493–511. [18] A. Olivera, S. Spiegel, Prostaglandins Other Lipid Mediat. 64 (2001) 123–134. [19] T.A. Taha, Y.A. Hannun, L.M. Obeid, J. Biochem. Mol. Biol. 39 (2006) 113–131. [20] B.W. Wattenberg, S.M. Pitson, D.M. Raben, J. Lipid Res. 47 (2006) 1128–1139. [21] H. Liu, M. Sugiura, V.E. Nava, L.C. Edsall, K. Kono, S. Poulton, S. Milstien, T. Kohama, S. Spiegel, J. Biol. Chem. 275 (2000) 19513–19520. [22] A. Olivera, T. Kohama, L. Edsall, V. Nava, O. Cuvillier, S. Poulton, S. Spiegel, J. Cell Biol. 147 (1999) 545–557. [23] N. Igarashi, T. Okada, S. Hayashi, T. Fujita, S. Jahangeer, S. Nakamura, J. Biol. Chem. 278 (2003) 46832–46839.
[24] H. Liu, R.E. Toman, S.K. Goparaju, M. Maceyka, V.E. Nava, H. Sankala, S.G. Payne, M. Bektas, I. Ishii, J. Chun, S. Milstien, S. Spiegel, J. Biol. Chem. 278 (2003) 40330–40336. [25] T. Okada, G. Ding, H. Sonoda, T. Kajimoto, Y. Haga, A. Khosrowbeygi, S. Gao, N. Miwa, S. Jahangeer, S. Nakamura, J. Biol. Chem. 280 (2005) 36318–36325. [26] T.A. Taha, K. Kitatani, M. El-Alwani, J. Bielawski, Y.A. Hannun, L.M. Obeid, FASEB J. 20 (2006) 482–484. [27] Y. Inagaki, P.Y. Li, A. Wada, S. Mitsutake, Y. Igarashi, Biochem. Biophys. Res. Commun. 311 (2003) 168–173. [28] S.M. Pitson, R.J. D'andrea, L. Vandeleur, P.A. Moretti, P. Xia, J.R. Gamble, M.A. Vadas, B.W. Wattenberg, Biochem. J. 350 (2000) 429–441. [29] N. Urtz, A. Olivera, E. Bofill-Cardonna, R. Csonga, A. Billich, D. Mechtcheriakova, F. Bornancin, M. Woisetschlager, J. Rivera, T. Baumruker, Mol. Cell. Biol. 24 (2004) 8765–8777. [30] S.M. Pitson, P.A. Moretti, J.R. Zebol, H.E. Lynn, P. Xia, M.A. Vadas, B.W. Wattenberg, EMBO J. 22 (2003) 5491–5500. [31] N.C. Hait, A. Bellamy, S. Milstien, T. Kordula, S. Spiegel, J. Biol. Chem. 282 (2007) 12058–12065. [32] G. Ding, H. Sonoda, H. Yu, T. Kajimoto, S.K. Goparaju, S. Jahangeer, T. Okada, S. Nakamura, J. Biol. Chem. 282 (2007) 27493–27502. [33] R.V. Stahelin, J.H. Hwang, J.H. Kim, Z.Y. Park, K.R. Johnson, L.M. Obeid, W. Cho, J. Biol. Chem. 280 (2005) 43030–43038. [34] C. Delon, M. Manifava, E. Wood, D. Thompson, S. Krugmann, S. Pyne, N.T. Ktistakis, J. Biol. Chem. 279 (2004) 44763–44774. [35] A. Olivera, J. Rosenthal, S. Spiegel, J. Cell. Biochem. 60 (1996) 529–537. [36] P. Xia, L. Wang, P.A. Moretti, N. Albanese, F. Chai, S.M. Pitson, R.J. D'Andrea, J.R. Gamble, M.A. Vadas, J. Biol. Chem. 277 (2002) 7996–8003. [37] S. Hayashi, T. Okada, N. Igarashi, T. Fujita, S. Jahangeer, S. Nakamura, J. Biol. Chem. 277 (2002) 33319–33324. [38] A. Olivera, T. Kohama, Z. Tu, S. Milstien, S. Spiegel, J. Biol. Chem. 273 (1998) 12576–12583. [39] R. Alemany, B. Kleuser, L. Ruwisch, K. Danneberg, H. Lass, R. Hashemi, S. Spiegel, K.H. Jakobs, D. Meyer zu Heringdorf, FEBS Lett. 509 (2001) 239–244. [40] T.Y. Chin, H.M. Hwang, S.H. Chueh, Mol. Pharmacol. 61 (2002) 486–494. [41] C.J. van Koppen, D. Meyer zu Heringdorf, R. Alemany, K.H. Jakobs, Life Sci. 68 (2001) 2535–2540. [42] A. Olivera, L. Edsall, S. Poulton, A. Kazlauskas, S. Spiegel, FASEB J. 13 (1999) 1593–1600. [43] C.M. Sutherland, P.A. Moretti, N.M. Hewitt, C.J. Bagley, M.A. Vadas, S.M. Pitson, J. Biol. Chem. 281 (2006) 11693–11701. [44] Y. Yatomi, F. Ruan, S. Hakomori, Y. Igarashi, Blood 86 (1995) 193–202. [45] R. Pappu, S.R. Schwab, I. Cornelissen, J.P. Pereira, J.B. Regard, Y. Xu, E. Camerer, Y.W. Zheng, Y. Huang, J.G. Cyster, S.R. Coughlin, Science 316 (2007) 295–298. [46] K. Ito, Y. Anada, M. Tani, M. Ikeda, T. Sano, A. Kihara, Y. Igarashi, Biochem. Biophys. Res. Commun. 357 (2007) 212–217. [47] P. Hänel, P. Andréani, M.H. Gräler, FASEB J. 21 (2007) 1202–1209. [48] T.K. Ghosh, J. Bian, D.L. Gill, Science 248 (1990) 1653–1656. [49] T.K. Ghosh, J. Bian, D.L. Gill, J. Biol. Chem. 269 (1994) 22628–22635. [50] D. Meyer zu Heringdorf, K. Liliom, M. Schaefer, K. Danneberg, J.H. Jaggar, G. Tigyi, K.H. Jakobs, FEBS Lett. 554 (2003) 443–449. [51] A. Titievsky, I. Titievskaya, M. Pasternack, K. Kaila, K. Törnquist, J. Biol. Chem. 273 (1998) 242–247. [52] T. Blom, N. Bergelin, J.P. Slotte, K. Tornquist, Cell. Signal. 18 (2006) 1366–1375. [53] C. Mathes, A. Fleig, R. Penner, J. Biol. Chem. 273 (1998) 25020–25030. [54] K. Itagaki, C.J. Hauser, J. Biol. Chem. 278 (2003) 27540–27547. [55] S. Borges, S. Lindstrom, C. Walters, A. Warrier, M. Wilson, J. Physiol. 586 (2008) 605–626. [56] S. Spiegel, O. Cuvillier, L.C. Edsall, T. Kohama, R. Menzeleev, Z. Olah, A. Olivera, G. Pirianov, D.M. Thomas, Z. Tu, J.R. Van Brocklyn, F. Wang, Ann. N. Y. Acad. Sci. 845 (1998) 11–18. [57] R.E. Toman, S. Spiegel, Neurochem. Res. 27 (2002) 619–627. [58] K. Watterson, H. Sankala, S. Milstien, S. Spiegel, Prog. Lipid Res. 42 (2003) 344–357. [59] S.E. Alvarez, S. Milstien, S. Spiegel, Trends Endocrinol. Metab. 18 (2007) 300–307. [60] H. Rosen, E.J. Goetzl, Nat. Rev. Immunol. 5 (2005) 560–570. [61] S.R. Schwab, J.G. Cyster, Nat. Immunol. 8 (2007) 1295–1301. [62] P.S. Jolly, M. Bektas, A. Olivera, C. Gonzalez-Espinosa, R.L. Proia, J. Rivera, S. Milstien, S. Spiegel, J. Exp. Med. 199 (2004) 959–970. [63] P. Mitra, C.A. Oskeritzian, S.G. Payne, M.A. Beaven, S. Milstien, S. Spiegel, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 16394–16399. [64] Z. Li, C.D. Aizenman, H.T. Cline, Neuron 33 (2002) 741–750. [65] T. Nakamura, M. Komiya, K. Sone, E. Hirose, N. Gotoh, H. Morii, Y. Ohta, N. Mori, Mol. Cell. Biol. 22 (2002) 8721–8734. [66] S. Estrach, S. Schmidt, S. Diriong, A. Penna, A. Blangy, P. Fort, A. Debant, Curr. Biol. 12 (2002) 307–312. [67] C. Donati, P. Bruni, Biochim. Biophys. Acta 1758 (2006) 2037–2048. [68] J.R. Van Brocklyn, Z. Tu, L.C. Edsall, R.R. Schmidt, S. Spiegel, J. Biol. Chem. 274 (1999) 4626–4632. [69] A.J. MacLennan, B.K. Devlin, L. Marks, A.A. Gaskin, K.L. Neitzel, N. Lee, Dev. Neurosci. 22 (2000) 283–295. [70] R.E. Toman, S.G. Payne, K.R. Watterson, M. Maceyka, N.H. Lee, S. Milstien, J.W. Bigbee, S. Spiegel, J. Cell Biol. 166 (2004) 381–392. [71] M. Murakami, M. Ichihara, S. Sobue, R. Kikuchi, H. Ito, A. Kimura, T. Iwasaki, A. Takagi, T. Kojima, M. Takahashi, M. Suzuki, Y. Banno, Y. Nozawa, T. Murate, J. Neurochem. 102 (2007) 1585–1594. [72] L. Strochlic, A. Dwivedy, F.P. van Horck, J. Falk, C.E. Holt, Development 135 (2008) 333–342.
T. Okada et al. / Cellular Signalling 21 (2009) 7–13 [73] C. McGiffert, J.J. Contos, B. Friedman, J. Chun, FEBS Lett. 531 (2002) 103–108. [74] Y. Liu, R. Wada, T. Yamashita, Y. Mi, C.X. Deng, J.P. Hobson, H.M. Rosenfeldt, V.E. Nava, S.S. Chae, M.J. Lee, C.H. Liu, T. Hla, S. Spiegel, R.L. Proia, J. Clin. Invest. 106 (2000) 951–961. [75] J. Harada, M. Foley, M.A. Moskowitz, C. Waeber, J. Neurochem. 88 (2004) 1026–1039. [76] K. Mizugishi, T. Yamashita, A. Olivera, G.F. Miller, S. Spiegel, R.L. Proia, Mol. Cell. Biol. 25 (2005) 11113–11121. [77] J. Mitoma, M. Ito, S. Furuya, Y. Hirabayashi, J. Neurosci. Res. 51 (1998) 712–722. [78] S.E. Ping, G.L. Barrett, J. Neurosci. Res. 54 (1998) 206–213. [79] K. Shinpo, S. Kikuchi, F. Moriwaka, K. Tashiro, Brain Res. 819 (1999) 170–173. [80] A.J. MacLennan, S.J. Benner, A. Andringa, A.H. Chaves, J.L. Rosing, R. Vesey, A.M. Karpman, S.A. Cronier, N. Lee, L.C. Erway, M.L. Miller, Hear. Res. 220 (2006) 38–48. [81] M. Kono, I.A. Belyantseva, A. Skoura, G.I. Frolenkov, M.F. Starost, J.L. Dreier, D. Lidington, S.S. Bolz, T.B. Friedman, T. Hla, R.L. Proia, J. Biol. Chem. 282 (2007) 10690–10696. [82] D.R. Herr, N. Grillet, M. Schwander, R. Rivera, U. Müller, J. Chun, J. Neurosci. 27 (2007) 1474–1478. [83] C.L. Chik, B. Li, T. Negishi, E. Karpinski, A.K. Ho, Endocrinology 140 (1999) 5682–5690. [84] A.J. MacLennan, P.R. Carney, W.J. Zhu, A.H. Chaves, J. Garcia, J.R. Grimes, K.J. Anderson, S.N. Roper, N. Lee, Eur. J. Neurosci. 14 (2001) 203–209. [85] T. Numakawa, H. Nakayama, S. Suzuki, T. Kubo, F. Nara, Y. Numakawa, D. Yokomaku, T. Araki, T. Ishimoto, A. Ogura, T. Taguchi, J. Biol. Chem. 278 (2003) 41259–41269. [86] Y.H. Zhang, G.D. Nicol, Neurosci. Lett. 366 (2004) 187–192. [87] Y.H. Zhang, M.R. Vasko, G.D. Nicol, J. Physiol. (2006). [88] T. Kajimoto, T. Okada, H. Yu, S. Goparaju, S. Jahangeer, S. Nakamura, Mol. Cell. Biol. 27 (2007) 3429–3440. [89] T. Kanno et al. Manuscript in preparation.
13
[90] H.A. Cameron, R.D. McKay, J. Comp. Neurol. 435 (2001) 406–417. [91] T.J. Shors, G. Miesegaes, A. Beylin, M. Zhao, T. Rydel, E. Gould, Nature 410 (2001) 372–376. [92] T. Ariga, W.D. Jarvis, R.K. Yu, J. Lipid Res. 39 (1998) 1–16. [93] C.L. Masters, G. Multhaup, G. Simms, J. Pottgiesser, R.N. Martins, K. Beyreuther, EMBO J. 4 (1985) 2757–2763. [94] B.A. Yankner, L.R. Dawes, S. Fisher, L. Villa-Komaroff, M.L. Oster-Granite, R.L. Neve, Science 245 (1989) 417–420. [95] T. Thomas, G. Thomas, C. McLendon, T. Sutton, M. Mullan, Nature 380 (1996) 168–171. [96] A. Jana, K. Pahan, J. Biol. Chem. 279 (2004) 51451–51459. [97] C. Zeng, J.T. Lee, H. Chen, S. Chen, C.Y. Hsu, J. Xu, J. Neurochem. 94 (2005) 703–712. [98] A.V. Alessenko, A.E. Bugrova, L.B. Dudnik, Biochem. Soc. Trans. 32 (2004) 144–146. [99] C. Garcia-Ruiz, A. Colell, M. Mari, A. Morales, J.C. Fernandez-Checa, J. Biol. Chem. 272 (1997) 11369–11377. [100] M. Maceyka, S. Milstien, S. Spiegel, Circ. Res. 100 (2007) 7–9. [101] D. Pchejetski, O. Kunduzova, A. Dayon, D. Calise, M.H. Seguelas, N. Leducq, I. Seif, A. Parini, O. Cuvillier, Circ. Res. 100 (2007) 41–49. [102] C. Ikonomidou, F. Bosch, M. Miksa, P. Bittigau, J. Vockler, K. Dikranian, T.L. Tenkova, V. Stefovska, L. Turski, J.W. Olney, Science 283 (1999) 70–74. [103] H. van Praag, A.F. Schinder, B.R. Christie, N. Toni, T.D. Palmer, F.H. Gage, Nature 415 (2002) 1030–1034. [104] M. Verhage, A.S. Maia, J.J. Plomp, A.B. Brussaard, J.H. Heeroma, H. Vermeer, R.F. Toonen, R.E. Hammer, T.K. van den Berg, M. Missler, H.J. Geuze, T.C. Sudhof, Science 287 (2000) 864–869.