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Neurotransmitters co-existing with VIP or PACAP
Peptides 25 (2004) 393–401
Review
Neurotransmitters co-existing with VIP or PACAP夽 Jan Fahrenkrug∗ , Jens Hannibal Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
Abstract It is now recognized that a neuron can produce, store and release more than one transmitter substance, and a number of examples of co-existing transmitters, particularly a neuropeptide together with a classical transmitter, have been reported. The present paper deals with transmitter substances, peptides or classical transmitters, co-existing with the two structurally related peptides VIP and PACAP and the possible functional implications of this co-existence. © 2004 Elsevier Inc. All rights reserved. Keywords: Co-existence; Co-release; Neuropeptides; Neurotransmitters; PACAP; VIP
1. Introduction
2. VIP and PACAP
During the last decades evidence has accumulated that a neuron can produce, store and release more than one transmitter substance [31]. Following synaptic release the multiple neurotransmitters may interact at the level of the receptor and/or second messengers before evoking a functional response. Some of the best examples of co-existing transmitters and their functional implications come from studies of the neuronal systems containing the neuropeptide vasoactive intestinal polypeptide (VIP). Our paper in Peptides [40] which demonstrates co-existence of peptide with N-terminal histidine and C-terminal isoleucine amide (PHI) and VIP in nerves regulating blood flow and bronchial smooth muscle tone is one of the first examples where the functional significance of co-existing peptide transmitters is elucidated. When dealing with co-existence and co-transmission involving multiple neurotransmitters the following combinations are in principle possible: (1) co-existence of classical transmitters; (2) co-existence of peptide(s) with classical transmitter(s); (3) co-existence of peptides derived from the same precusor; and (4) co-existence of peptides derived from separate precursors. In the present review we will focus on the co-existence of the two structurally related peptides VIP and pituitary adenylate cyclase activating peptide (PACAP) with other peptide transmitters or classical transmitters.
VIP, a 28-amino-acid polypeptide, was originally isolated from porcine small intestine [62] whereas PACAP was first isolated from ovine hypothalamus discovered on the basis of its ability to increase adenylate cyclase activity in rat pituitary cells [50]. PACAP occurs as two variants: PACAP-38 (a 38-amino-acid polypeptide) and a C-terminally truncated form, PACAP-27, both of which share amino acid homology with VIP at their N-terminus. Both VIP and PACAP belong to the glucagon/secretin superfamily of peptides and are widely expressed in the central nervous system as well as in peripheral neurons [10,73]. Both peptides have a broad spectrum of biological functions including neurotransmitter, secretagogue, neuroprotective, neurotrophic and differentiation roles as well as effect on growth and survival of cells in the developing nervous system [2,3,10,18,29,37,38,59,72–74]. VIP is derived from a precursor, prepro-VIP, consisting of 170 amino acid residues (Fig. 1A). The precursor contains besides VIP another biologically active peptide, PHI in its sequence [33,54]. PHI is structurally related to VIP and shares many of its biological actions, although in most systems less potent than VIP. Processing of the VIP precursor can follow an alternative pathway in which the dibasic cleavage site after PHI is uncleavaged resulting in a C-terminally extended form, PHV, which is found to be just as potent as VIP in relaxing smooth muscle activity [57,77]. PACAP is derived from a 175-amino-acid precursor, prepro-PACAP (Fig. 1B), which in its sequence contains a PACAP-related peptide, PRP [55]. This peptide displays sequence similarities to PACAP and the other members of the VIP/PACAP/Glucagon/Secretin family.
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DOI of original article: 10.1016/0196-9781(84)90090-1. Corresponding author. Tel.: +45-3531-2640; fax: +45-3531-2099. E-mail address: [email protected] (J. Fahrenkrug).
∗
0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.01.010
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Co-existence of Peptide HI (PHI) and VIP in nerves regulating blood flow and bronchial smooth muscle tone in various mammals including man Jan M. Lundberg, Jan Fahrenkrug, Tomas Hökfelt, Claes-Roland Martling, Olof Larsson, Kazuhiko Tatemoto, Anders Änggård Peptides, 1984;5:593–606 Abstract By immunohistochemistry it was found that PHIand VIP-like immunoreactivity (-IR) occured in the same autonomic neurons in the upper respiratory tract, tongue and salivary glands with associated ganglia in rat, guinea-pig, cat, pig and man. VIP- and PHI-like immunoreactivity was also found in similar locations in the human heart. The N-terminally directed, but not the C-terminally directed, PHI antiserum or the VIP antiserum stained endocrine cells in the pig duodenum. This suggests the existence of an additional PHI-like peptide. Ligation of nerves acutely caused marked overlapping axonal accumulations of PHI- and VIP-IR central to the lesion. Two weeks after transection of the nerves, both types of immunoreactivities were still observed in accumulations both in the axons as well as in the corresponding cell bodies. The levels of PHIand VIP-IR in normal tissues from the cat were around 10–50 pmol/g with a molar ratio of about 1 to 2. Systemic administration of PHI and VIP induced hypotension, probably due to peripheral vasodilatation in both guinea-pig and cat. Furthermore, both PHI and VIP caused an inhibition of the vegally induced increase in respiratory insufflation pressure in guinea-pig. PHI and VIP relaxed the guinea-pig trachea in vitro, suggesting a direct action on tracheobronchial smooth muscle. VIP was about 5–10 times more potent than PHI with regard to hypotensive effects and 2–3-fold, considering respiratory smooth muscle-relaxant effects in the guinea-pig. PHI was about 50-fold less potent to induce hypotension in the cat than in the guinea-pig. Although species differences seem to exist as regards biological potency, PHI should also be considered when examining the role of VIP as an autonomic neurotransmitter. Keywords: Vasoactive intestinal peptide (VIP); Peptide histidine isoleucine (PHI); Immunohistochemistry; Mammals
3. Co-existence of VIP and PHI, two structurally related peptides derived from the same precursor PHI was isolated in 1980 by means of a chemical method to detect C-terminal amides [67]. Subsequently specific antibodies for radioimmunochemical measurements and localization of PHI by immunohistochemistry were gen-
erated. Immunoreactive PHI was found in tissue extract with a distribution which paralleled that of immunoreactive VIP [4,5,11,40,48,58,76]. By immunohistochemistry the two peptides were found to be co-localized in neuronal cell bodies and nerve fibers in the central nervous system (Fig. 2A–C), the gastrointestinal tract, the pancreas, the reproductive and respiratory systems and autonomic ganglia [4,11,30,40,48,58]. When the cDNA complimentary to the mRNA encoding the VIP precursor was subsequently cloned, an explanation for the co-existence of VIP and PHI was offered [33]. The amino acid sequence of the VIP precursor was found to contain PHI in addition to VIP. One would expect a one-to-one molar ratio between the tissue concentrations of VIP and PHI but the ratio varies between regions, probably due to differences in posttranslational processing [11]. However, upon activation of the VIP containing neurons, VIP and PHI are co-released mainly in equimolar amounts (Fig. 3A) [4,9,30,41]. The functional significance of the co-release of VIP and PHI is not fully understood. VIP and PHI mediate a number of physiological actions in many systems such as autonomic nervous control of blood flow, smooth muscle activity and secretion in the digestive tract, respiratory tract and urogenital tract [10]. The potencies of administered PHI are, however, in most systems orders of magnitude lower than those of VIP (Fig. 3B) [9,32,40,52,58,65,66,78] and PHI has thus been considered a weak agonist for VIP receptors. Until now two VIP receptors termed VPAC1 and VPAC2 , have been cloned which exhibit high affinity for both VIP and PACAP [27]. A third receptor, termed PAC1 , that possesses high affinity for PACAP but a much lower affinity for VIP has also been cloned and characterized [27]. Up till now a selective PHI receptor has not been identified in mammals and it is generally accepted that the effects of PHI are mediated through the VIP receptors. There are, however, examples indicating that the biological responses to PHI are distinct from those evoked by VIP, and recently the first PHI receptor was isolated and characterized in goldfish [70]. An area which has attracted much attention during the last years is the role of VIP in the brain’s biological clock located in the hypothalamic suprachiasmatic nucleus. VIP and PHI are highly expressed within neurons in the retinorecipient area of the suprachiasmatic nucleus (the light responsive cells) (Fig. 2A–C) [48]. In studies of VIP and PHI deficient mice or VPAC2 receptor knock-out mice it has clearly been demonstrated that VIP/PHI and the VPAC2 receptor are essential for sustained rhythm generation in the suprachiasmatic nucleus [6,28]. The mechanism by which VIP and PHI influences circadian function in the suprachiasmatic nucleus remains, however, to be clarified. 4. Co-existence of PACAP and PRP, two structurally related peptides derived from the same precursor The cDNA encoding the PACAP precursor has been characterized in a number of mammalian species [34,55,56].
J. Fahrenkrug, J. Hannibal / Peptides 25 (2004) 393–401
(A)
21 S
SIGNAL PEPTIDE
22 Q
80 R
108 109 110 G K R
PREPRO-VIP 22-79
PHI
SIGNAL PEPTIDE
123 124 K R
111-22
PHI
395 153 154 155 G K R
VIP
156-70
111-22
PREPRO-VIP 22-79
VIP
156-70
PHV
(B)
24 S
SIGNAL PEPTIDE
25 S
79 R
80 R
110 A
111 R
129 130 K R
158 159 160 169 170 171 G K R G RR
PACAP
PRP
"big PRP"
SIGNAL PEPTIDE
PRP
PACAP38
PACAP27
Fig. 1. Schematic representation of the structure of rat prepro-VIP (A) and rat prepro-PACAP (B) and their processing products. Amino acid residues at posttranslational processing sites are shown (A: alanine, G: glycine, K: lysine, Q: glutamine, R: arginine, S: serine). Abbreviations: PACAP, pituitary adenylate cyclase activating polypeptide; PHI, peptide with N-terminal histidine and C-terminal isoleucine amide; PHV, peptide with N-terminal histidine and C-terminal valine; PRP, PACAP related peptide; VIP, vasoactive intestinal polypeptide.
The overall organization of the PACAP precursor exhibits similarities with that of the VIP precursor and like the VIP precursor prepro-PACAP contains another peptide in its sequence located upstream of PACAP-38 (Fig. 1B). This peptide which exhibits moderate structural homology with PACAP-27 has been termed PACAP related peptide (PRP) [34,55]. It has been shown using specific radioimmunoassays for PACAP-38, PACAP-27 and PRP combined with high pressure liquid chromatography that all three PACAP precursor-derived peptides are detectable in tissue extracts from various brain regions, the gastrointestinal tract, the urogenital tract and testes [13,14,22,23,25]. Surprisingly the not fully processed form of PACAP, PACAP-38, is the dominating peptide in all tissues examined. The tissue concentrations of PACAP-27 and PRP amount only 7–20 and 1–10% of that of PACAP-38, respectively [14,23]. By immunohistochemistry a complete co-localization of PRP and PACAP has been demonstrated in all PACAP containing cells examined so far (Fig. 2D–F) [25,49]. Whether this co-existence is of functional significance and whether PRP, PACAP-27 and PACAP-38 are co-released or
co-secreted remains to be solved. The effects of PACAP-38 and PACAP-27 are well described and are in most biological systems identical [73]. Our knowledge of PRP’s biological actions is, however, limited. A few studies have demonstrated that PRP has similar effects as PACAP but displays much lower potency, while the extended form of PRP, named big PRP, has limited biological actions [35,75].
5. Co-existence of VIP and PACAP, two structurally related peptides derived from separate precursors The distributions of VIP and PACAP in the central nervous system are substantially different and PACAP is much more widely distributed than VIP [7,20,39]. In the brain the two peptides have only been demonstrated to co-exist in a few cortical neurons [15]. In contrast to the central nervous system VIP and PACAP often appear to be co-localized in the same nerve cell bodies and nerve fibers in peripheral organs. In the mammalian gastrointestinal tract VIP
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Fig. 2. (A–C) Confocal photomicrograph showing co-localization of VIP (A) and PHI (B) (merged image C) in nerve cell bodies and fibers in a coronal section through rat suprachiasmatic nucleus. oc: optic chiasma. (D–F) Confocal photomicrograph showing co-localization of PACAP (D) and PRP (E) (merged image F) in nerve cell bodies and fibers in a coronal section of paraventricular nucleus from colchicine pretreated rat. 3v: third ventricle.
and PACAP are often found to be co-stored in nerve cell bodies and nerve fibers located in the myenteric and in the submucosal plexa of the small and large intestine (Fig. 4C and D) as well as in the myenteric cell bodies and fibers of the esophagus and gastric antrum [22,60,68]. In the gastrointestinal tract PACAP modulates motility and secretion, effects which exhibit a location-dependent variation [47]. Many of the actions are shared with VIP suggesting that the two peptides could be co-mediators. In addition VIP and PACAP are co-stored in neuroendocrine tumor cells [12] and in parasympathetic ganglia such as sphenopalatine, the otic, the jugular nodose, the ciliary and the submandibular ganglia [53,64] and in ganglia innervating the lung, the urogenital tract, the adrenals, the eye and in nerve fibers innervating the sweat glands [13,14,63,69,71]. Co-localization of VIP and PACAP is also seen in dorsal root ganglia after axotomy [79] and in the sympathetic superior cervical ganglion following preganglionic denervation [17]. In these ganglia the increase in PACAP expression after denervation is rapid and transient, while elevated VIP expression occurs much later suggesting the two peptides play a complementary functional role during neuronal regeneration. Since most target areas for VIP and PACAP express both the PACAP specific PAC1 receptor and the VIP/PACAP shared VPAC1 and VPAC2 receptors, detailed studies using receptor specific agonists and antagonists are necessary to clarify the
role of VIP and PACAP in the various parts of the nervous system.
6. Co-existence of VIP with the classical transmitter acetylcholine The evidence for co-localization of VIP and acetylcholine in a population of autonomic postganglionic neurons comes from studies demonstrating that the VIP immunoreactive cells contain high levels of acetylcholineesterase (Fig. 4A and B) [46] and the acetylcholine synthesizing enzyme, choline acetyltransferase [45]. Furthermore the ultra structural features of the VIP immunoreactive nerves have been shown to be similar to those of cholinergic nerves, i.e. a dominance of small clear vesicles (diameter ∼500 Å) which seem to store most of the acetylcholine and a few larger dense core vesicles (diameter ∼1000 Å) in which VIP is preferentially localized [42]. The immunoelectron microscopic studies have been supported by biochemical subcellular fractionation experiments which also disclosed that on a molar basis there are several hundred times as much acetylcholine as VIP [42]. The postganglionic parasympathetic nerves innervating blood vessels and exocrine elements of the cat submandibular gland have been used for functional analysis of the co-existence of VIP and acetylcholine [44]. Activation of these nerves causes salivary secretion and concomitant
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induce both salivation and vasodilation. At high frequency stimulation, however, the vasodilation is atropine-resistant, most likely mediated by the release of VIP. Although VIP is an atropine-resistant vasodilator in the submandibular gland the peptide does not alone provoke secretion. VIP can, however, potentiate the acetylcholine induced salivary secretion. Thus acetylcholine and VIP have complementary actions on the functional response in the salivary gland. For the secretory response acetylcholine acts as a neurotransmitter in the classical sense, while VIP serves as neuromodulator. In addition, both acetylcholine and VIP may be transmitters for the vasodilation. In vitro studies support an interaction between VIP and acetylcholine directly on the secretory cells since VIP in nanomolar concentrations can enhance the association rate of muscarinic ligand binding to membranes of the submandibular salivary gland [43]. Furthermore, carbachol enhances the cAMP formation induced by VIP which suggests interaction between acetylcholine and VIP at the second messenger level as well [16].
7. Co-existence of PACAP with the classical transmitter glutamate
Fig. 3. (A) Co-release of VIP and PHI during transmural electrical nerve stimulation (10 Hz, 2 ms, 150 mA for the period indicated by hatched bars) of smooth muscle strips from the corpus (upper panel) and antral part of the porcine stomach (lower panel). The peptide release was accompanied by a non-adrenergic, non-cholinergic smooth muscle relaxation. The solid line represents VIP immunoreactivity, the dashed line PHI immunoreactivity. (B) Dose–response curves for relaxant effects of VIP (䊉) and PHI () on spontaneous muscle activity of porcine gastric antrum in vitro. The effect is given as changes in amplitude expressed as the percentage of controls, i.e. no inhibition equals 0% and total relaxation equals 100%. Figures are given as the mean SEM of five experiments (from [9]).
increase in local blood flow. The nervous activation also causes an overflow of both acetylcholine and VIP into the venous effluent from the gland indicating co-release, and the VIP release is frequency-dependant being highest at high frequency stimulation. Both secretion and vasodilation are potentiated by inhibition of acetylcholineesterase and abolished by atropine at low frequency stimulation of the parasympathetic nerves supplying the submandibular gland. Thus acetylcholine is a prerequisite for salivation but could also be of importance for the increase in blood flow consistent with the finding that administration of acetylcholine can
The brain’s biological clock, which generates circadian rhythm of physiology and behavior, is as mentioned located in the suprachiasmatic nucleus [36]. The molecular machinery driving the circadian clock consists of a group of “clock genes” which in double autoregulatory feedback loops interact and control their own transcription within the neurons of the suprachiasmatic nucleus [61]. The clock is daily adjusted to the environmental light/dark cycle, but the mechanism by which external light modifies the activity of the neurons in the suprachiasmatic nucleus is still incompletely understood [61]. The light signaling pathway originates in a small population of retinal ganglion cells that project to the suprachiasmatic nucleus via the retino-hypothalamic tract [51]. These neurons are characterized by the expression of the circadian photopigment melanopsin [24] and co-store both the classical neurotransmitter glutamate and PACAP (Fig. 4E and F) [26]. Glutamate has for years been considered an important mediator of adjustment in circadian timing in response to light [8], but recent studies indicate that glutamate and PACAP both play a role in a rather complex functional interplay [19]. Thus PACAP in nanomolar concentrations can phase-shift the endogenous rhythm of the biological clock similar to light and glutamate whereas PACAP in micromolar concentrations modulates glutamate induced phase-shifting of the clock. Recent in vivo studies using a PAC1 receptor antagonist or mutant mice lacking the PAC1 receptor have shown that this receptor plays a role in modulating light induced resetting of circadian rhythm and light induced “clock gene” expression in the suprachiasmatic nucleus [1,21].
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Fig. 4. (A, B) Consecutive sections of cat submandibular ganglion immunostaining for VIP and stained for acetylcholineesterase (AchE) indicating that VIP and acetylcholine occur in the same neurons (kindly provided by J. Lundberg). (C, D) Double immunostaining of section of rat small intestine showing co-localization of PACAP and VIP in nerve cell body (large arrow) and fibers (small arrows) in the myenteric (mye) and submucosal plexa (sub). PACAP containing neuron lacking VIP, but innervated by VIP is indicated by arrowhead. (E, F) Double immunostaining of sagittal section of rat retina showing that PACAP is co-localized with glutamate in a subpopulation of ganglionic cells (large arrows) and their processes (small arrows). Abbreviations: GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; ONL, outer nuclear layer (from [26]).
8. Concluding remarks In the present paper we have presented a number of examples where neurons containing VIP or PACAP have been shown to contain another substance, possibly involved in the process of chemical transmission at synapses. The existence of multiple transmitters and their simultaneous or sequential release require multiple forms of recep-
tors on both postsynaptic and presynaptic membranes. A number of possibilities exist how the co-existing transmitters may work together and evoke diverse physiological responses: (1) Both transmitters may cross the synaptic cleft and exert their action via stimulation of either the same or different receptors on the postsynaptic cell.
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(2) One transmitter may activate receptors on the postsynaptic cells whereas the other transmitter blocks another type of receptor. (3) One transmitter may act on the postsynaptic cells whereas the other transmitter may exert its action on presynaptic autoreceptors. (4) One transmitter may act on the postsynaptic cell whereas the other transmitter may act on presynaptic receptors located on nerve endings of other neurons. (5) One transmitter may act on one cell type and the other transmitter on another cell type in the target organ. The mere demonstration that two transmitter substances are co-localized in the same neuron does, however, not necessarily mean that they function as co-transmitters. The substances must be demonstrated to be co-released during physiological activation of the neurons and exert pre- or postsynaptic actions. The co-localization of peptides in the same neuron which are synthesized from the same precursor could imply a functional role but some of the peptides may just represent inactive split products. Although the functional significance of the co-existence of peptides and classical neurotransmitters is not fully elucidated, it seems that the role of the peptide is to modify the effect caused by the classical transmitters. It is possible that a classical transmitter system can be subdivided on the basis of co-existence with specific peptides. The release of the peptide and classical transmitter upon nervous activation may depend on the intensity of stimulation (the peptide release requires a higher stimulation frequency) and often the peptide seems to be responsible for the component of the biological response characterized by slow onset and long duration. Future research will hopefully define more exactly the interactions between peptide and classical transmitter. Furthermore it will be relevant to analyze to what extent the balance among multiple synaptic transmitters is disturbed during various nervous disorders and how neuroactive drugs may affect the interplay of multiple transmitters.
Acknowledgments The study was supported by The Danish Biotechnology Center for Cellular Communication.
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[44] Lundberg JM, Hedlund B, Änggård A, Fahrenkrug J, Hökfelt T, Tatemoto K, et al. Costorage of peptides and classical transmitters in neurons. In: Bloom SR, Polak JM, Lindenlaub E, editors. Systemic role of regulatory peptides. Stuttgart: Schattauer-Verlag; 1982. p. 93–119. [45] Lundberg JM, Änggård A, Emson P, Fahrenkrug J, Hökfelt T. VIPergic and cholinergic mechanisms in the cat nasal mucosa: studies on choline acetyltransferase and release of VIP. Proc Natl Acad Sci USA 1981;78:5255–9. [46] Lundberg JM, Änggård A, Fahrenkrug J, Hökfelt T, Mutt V. Vasoactive intestinal polypeptide (VIP) in cholinergic neurons of exocrine glands: functional significance of coexisting transmitters for vasodilation and secretion. Proc Natl Acad Sci USA 1980;77:1651–5. [47] Läuffer JM, Modlin IR, Tang LH. Biological relevance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the gastrointestinal tract. Regul Pept 1999;84:1–12. [48] Mikkelsen JD, Fahrenkrug J. Concentrations and distribution of vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and peptide histidine valine (PHV) in the cerebral cortex and the suprachiasmatic nucleus of the mouse brain. Brain Res 1994;656:95– 107. [49] Mikkelsen JD, Hannibal J, Fahrenkrug J, Larsen PJ, Olcese J, McArdle C. Pituitary adenylate cyclase activating peptide-38 (PACAP-38), PACAP-27, and PACAP related peptide (PRP) in the rat mediam eminence and pituitary. J Neuroendocrinol 1995;7:47–55. [50] Miyata A, Arimura A, Dahl RR, Uehara A, Jiang L, Culler MD, et al. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 1989;164:567–74. [51] Moore RY, Speh JC, Card JP. The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. J Comp Neurol 1995;352:351–66. [52] Moriarty KJ, Hegarty JE, Tatemoto K, Mutt V, Christofides ND, Bloom SR, et al. Effect of peptide histidine isoleucine on water and electrolyte transport in the human jejunum. Gut 1984;25:624–8. [53] Mulder H, Uddman R, Moller K, Elsås T, Ekblad E, Alumets J, et al. Pituitary adenylate cyclase activating polypeptide is expressed in autonomic neurons. Regul Pept 1995;59:121–8. [54] Nishizawa M, Hayakawa Y, Yanaihara N, Okamoto H. Nucleotide sequence divergence and functional constraint in VIP precursor mRNA evolution between human and rat. FEBS Lett 1985;183:55–9. [55] Ogi K, Kimura C, Onda H, Arimura A, Fujino M. Molecular cloning and characterization of cDNA for the precursor of rat pituitary adenylate cyclase activating polypeptide (PACAP). Biochem Biophys Res Commun 1990;173:1271–9. [56] Okazaki K, Itoh Y, Ogi K, Ohkubo S, Onda H. Characterization of murine PACAP mRNA. Peptides 1995;16:1295–9. [57] Palle C, Ottesen B, Fahrenkrug J. Peptide histidine valine (PHV) is present and biologically active in the human female genital tract. Regul Pept 1992;38:101–9. [58] Palle C, Ottesen B, Jørgensen J, Fahrenkrug J. Peptide histidine methionine and vasoactive intestinal peptide: occurrence and relaxant effect in the human female reproductive tract. Biol Reprod 1989;41:1103–11. [59] Pincus DW, DiCicco-Bloom EM, Black IB. Vasoactive intestinal peptide regulates mitosis, differentiation and survival of cultured sympathetic neuroblasts. Nature 1990;343:564–7. [60] Portbury AL, McConalogue K, Furness JB, Young HM. Distribution of pituitary adenylyl cyclase activating peptide (PACAP) immunoreactivity in neurons of the guinea-pig digestive tract and their projections in the ileum and colon. Cell Tissue Res 1995;279: 385–92. [61] Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002;418:935–41. [62] Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science 1970;169:1217–8.
J. Fahrenkrug, J. Hannibal / Peptides 25 (2004) 393–401 [63] Skakkebæk M, Hannibal J, Fahrenkrug J. Pituitary adenylate cyclase activating polypeptide (PACAP) in the rat mammary gland. Cell Tissue Res 1999;298:153–9. [64] Sundler F, Ekblad E, Hannibal J, Moller K, Zhang YZ, Mulder H, et al. Pituitary adenylate cyclase activating peptide in sensory and autonomic ganglia: localization and regulation. Ann NY Acad Sci 1996;805:410–28. [65] Suzuki Y, Satoh S, Lederis K, Rorstad O. Cerebral vascular effects of peptide histidine methionine in canine and bovine species. Pharmacology 1991;42:241–5. [66] Tapia-Arancibia L, Reichlin S. Vasoactive intestinal peptide and PHI stimulate somatostatin release from rat cerebral cortical and diencephalic cells in dispersed cell culture. Brain Res 1988;336:67–72. [67] Tatemoto K, Mutt V. Isolation and characterization of the intestinal peptide procine PHI (PHI-27), a new member of the glucagonsecretin family. Proc Natl Acad Sci USA 1981;78:6603–7. [68] Tornøe K, Hannibal J, Georg B, Schmidt PT, Hilsted L, Fahrenkrug J, et al. PACAP 1–38 as neurotransmitter in the porcine antrum. Regul Pept 2001;101:109–21. [69] Tornøe K, Hannibal J, Jensen TB, Georg B, Rickelt LF, Andreasen MB, et al. PACAP-(1–38) as neurotransmitter in the porcine adrenal glands. Am J Physiol Endocrinol Metab 2000;279:E1413–25. [70] Tse DLY, Pang RTK, Wong AOL, Chan S-M, Vaudry H, Chow BKC. Identification of a potential receptor for both peptide histidine isoleucine and peptide histidine valine. Endocrinology 2002;143:1327–36. [71] Uddman R, Luts A, Arimura A, Sundler F. Pituitary adenylate cyclase-activating peptide (PACAP), a new vasoactive intestinal peptide (VIP)-like peptide in the respiratory tract. Cell Tissue Res 1991;265:197–201.
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Review
Neurotransmitters co-existing with VIP or PACAP夽 Jan Fahrenkrug∗ , Jens Hannibal Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
Abstract It is now recognized that a neuron can produce, store and release more than one transmitter substance, and a number of examples of co-existing transmitters, particularly a neuropeptide together with a classical transmitter, have been reported. The present paper deals with transmitter substances, peptides or classical transmitters, co-existing with the two structurally related peptides VIP and PACAP and the possible functional implications of this co-existence. © 2004 Elsevier Inc. All rights reserved. Keywords: Co-existence; Co-release; Neuropeptides; Neurotransmitters; PACAP; VIP
1. Introduction
2. VIP and PACAP
During the last decades evidence has accumulated that a neuron can produce, store and release more than one transmitter substance [31]. Following synaptic release the multiple neurotransmitters may interact at the level of the receptor and/or second messengers before evoking a functional response. Some of the best examples of co-existing transmitters and their functional implications come from studies of the neuronal systems containing the neuropeptide vasoactive intestinal polypeptide (VIP). Our paper in Peptides [40] which demonstrates co-existence of peptide with N-terminal histidine and C-terminal isoleucine amide (PHI) and VIP in nerves regulating blood flow and bronchial smooth muscle tone is one of the first examples where the functional significance of co-existing peptide transmitters is elucidated. When dealing with co-existence and co-transmission involving multiple neurotransmitters the following combinations are in principle possible: (1) co-existence of classical transmitters; (2) co-existence of peptide(s) with classical transmitter(s); (3) co-existence of peptides derived from the same precusor; and (4) co-existence of peptides derived from separate precursors. In the present review we will focus on the co-existence of the two structurally related peptides VIP and pituitary adenylate cyclase activating peptide (PACAP) with other peptide transmitters or classical transmitters.
VIP, a 28-amino-acid polypeptide, was originally isolated from porcine small intestine [62] whereas PACAP was first isolated from ovine hypothalamus discovered on the basis of its ability to increase adenylate cyclase activity in rat pituitary cells [50]. PACAP occurs as two variants: PACAP-38 (a 38-amino-acid polypeptide) and a C-terminally truncated form, PACAP-27, both of which share amino acid homology with VIP at their N-terminus. Both VIP and PACAP belong to the glucagon/secretin superfamily of peptides and are widely expressed in the central nervous system as well as in peripheral neurons [10,73]. Both peptides have a broad spectrum of biological functions including neurotransmitter, secretagogue, neuroprotective, neurotrophic and differentiation roles as well as effect on growth and survival of cells in the developing nervous system [2,3,10,18,29,37,38,59,72–74]. VIP is derived from a precursor, prepro-VIP, consisting of 170 amino acid residues (Fig. 1A). The precursor contains besides VIP another biologically active peptide, PHI in its sequence [33,54]. PHI is structurally related to VIP and shares many of its biological actions, although in most systems less potent than VIP. Processing of the VIP precursor can follow an alternative pathway in which the dibasic cleavage site after PHI is uncleavaged resulting in a C-terminally extended form, PHV, which is found to be just as potent as VIP in relaxing smooth muscle activity [57,77]. PACAP is derived from a 175-amino-acid precursor, prepro-PACAP (Fig. 1B), which in its sequence contains a PACAP-related peptide, PRP [55]. This peptide displays sequence similarities to PACAP and the other members of the VIP/PACAP/Glucagon/Secretin family.
夽
DOI of original article: 10.1016/0196-9781(84)90090-1. Corresponding author. Tel.: +45-3531-2640; fax: +45-3531-2099. E-mail address: [email protected] (J. Fahrenkrug).
∗
0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.01.010
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Co-existence of Peptide HI (PHI) and VIP in nerves regulating blood flow and bronchial smooth muscle tone in various mammals including man Jan M. Lundberg, Jan Fahrenkrug, Tomas Hökfelt, Claes-Roland Martling, Olof Larsson, Kazuhiko Tatemoto, Anders Änggård Peptides, 1984;5:593–606 Abstract By immunohistochemistry it was found that PHIand VIP-like immunoreactivity (-IR) occured in the same autonomic neurons in the upper respiratory tract, tongue and salivary glands with associated ganglia in rat, guinea-pig, cat, pig and man. VIP- and PHI-like immunoreactivity was also found in similar locations in the human heart. The N-terminally directed, but not the C-terminally directed, PHI antiserum or the VIP antiserum stained endocrine cells in the pig duodenum. This suggests the existence of an additional PHI-like peptide. Ligation of nerves acutely caused marked overlapping axonal accumulations of PHI- and VIP-IR central to the lesion. Two weeks after transection of the nerves, both types of immunoreactivities were still observed in accumulations both in the axons as well as in the corresponding cell bodies. The levels of PHIand VIP-IR in normal tissues from the cat were around 10–50 pmol/g with a molar ratio of about 1 to 2. Systemic administration of PHI and VIP induced hypotension, probably due to peripheral vasodilatation in both guinea-pig and cat. Furthermore, both PHI and VIP caused an inhibition of the vegally induced increase in respiratory insufflation pressure in guinea-pig. PHI and VIP relaxed the guinea-pig trachea in vitro, suggesting a direct action on tracheobronchial smooth muscle. VIP was about 5–10 times more potent than PHI with regard to hypotensive effects and 2–3-fold, considering respiratory smooth muscle-relaxant effects in the guinea-pig. PHI was about 50-fold less potent to induce hypotension in the cat than in the guinea-pig. Although species differences seem to exist as regards biological potency, PHI should also be considered when examining the role of VIP as an autonomic neurotransmitter. Keywords: Vasoactive intestinal peptide (VIP); Peptide histidine isoleucine (PHI); Immunohistochemistry; Mammals
3. Co-existence of VIP and PHI, two structurally related peptides derived from the same precursor PHI was isolated in 1980 by means of a chemical method to detect C-terminal amides [67]. Subsequently specific antibodies for radioimmunochemical measurements and localization of PHI by immunohistochemistry were gen-
erated. Immunoreactive PHI was found in tissue extract with a distribution which paralleled that of immunoreactive VIP [4,5,11,40,48,58,76]. By immunohistochemistry the two peptides were found to be co-localized in neuronal cell bodies and nerve fibers in the central nervous system (Fig. 2A–C), the gastrointestinal tract, the pancreas, the reproductive and respiratory systems and autonomic ganglia [4,11,30,40,48,58]. When the cDNA complimentary to the mRNA encoding the VIP precursor was subsequently cloned, an explanation for the co-existence of VIP and PHI was offered [33]. The amino acid sequence of the VIP precursor was found to contain PHI in addition to VIP. One would expect a one-to-one molar ratio between the tissue concentrations of VIP and PHI but the ratio varies between regions, probably due to differences in posttranslational processing [11]. However, upon activation of the VIP containing neurons, VIP and PHI are co-released mainly in equimolar amounts (Fig. 3A) [4,9,30,41]. The functional significance of the co-release of VIP and PHI is not fully understood. VIP and PHI mediate a number of physiological actions in many systems such as autonomic nervous control of blood flow, smooth muscle activity and secretion in the digestive tract, respiratory tract and urogenital tract [10]. The potencies of administered PHI are, however, in most systems orders of magnitude lower than those of VIP (Fig. 3B) [9,32,40,52,58,65,66,78] and PHI has thus been considered a weak agonist for VIP receptors. Until now two VIP receptors termed VPAC1 and VPAC2 , have been cloned which exhibit high affinity for both VIP and PACAP [27]. A third receptor, termed PAC1 , that possesses high affinity for PACAP but a much lower affinity for VIP has also been cloned and characterized [27]. Up till now a selective PHI receptor has not been identified in mammals and it is generally accepted that the effects of PHI are mediated through the VIP receptors. There are, however, examples indicating that the biological responses to PHI are distinct from those evoked by VIP, and recently the first PHI receptor was isolated and characterized in goldfish [70]. An area which has attracted much attention during the last years is the role of VIP in the brain’s biological clock located in the hypothalamic suprachiasmatic nucleus. VIP and PHI are highly expressed within neurons in the retinorecipient area of the suprachiasmatic nucleus (the light responsive cells) (Fig. 2A–C) [48]. In studies of VIP and PHI deficient mice or VPAC2 receptor knock-out mice it has clearly been demonstrated that VIP/PHI and the VPAC2 receptor are essential for sustained rhythm generation in the suprachiasmatic nucleus [6,28]. The mechanism by which VIP and PHI influences circadian function in the suprachiasmatic nucleus remains, however, to be clarified. 4. Co-existence of PACAP and PRP, two structurally related peptides derived from the same precursor The cDNA encoding the PACAP precursor has been characterized in a number of mammalian species [34,55,56].
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(A)
21 S
SIGNAL PEPTIDE
22 Q
80 R
108 109 110 G K R
PREPRO-VIP 22-79
PHI
SIGNAL PEPTIDE
123 124 K R
111-22
PHI
395 153 154 155 G K R
VIP
156-70
111-22
PREPRO-VIP 22-79
VIP
156-70
PHV
(B)
24 S
SIGNAL PEPTIDE
25 S
79 R
80 R
110 A
111 R
129 130 K R
158 159 160 169 170 171 G K R G RR
PACAP
PRP
"big PRP"
SIGNAL PEPTIDE
PRP
PACAP38
PACAP27
Fig. 1. Schematic representation of the structure of rat prepro-VIP (A) and rat prepro-PACAP (B) and their processing products. Amino acid residues at posttranslational processing sites are shown (A: alanine, G: glycine, K: lysine, Q: glutamine, R: arginine, S: serine). Abbreviations: PACAP, pituitary adenylate cyclase activating polypeptide; PHI, peptide with N-terminal histidine and C-terminal isoleucine amide; PHV, peptide with N-terminal histidine and C-terminal valine; PRP, PACAP related peptide; VIP, vasoactive intestinal polypeptide.
The overall organization of the PACAP precursor exhibits similarities with that of the VIP precursor and like the VIP precursor prepro-PACAP contains another peptide in its sequence located upstream of PACAP-38 (Fig. 1B). This peptide which exhibits moderate structural homology with PACAP-27 has been termed PACAP related peptide (PRP) [34,55]. It has been shown using specific radioimmunoassays for PACAP-38, PACAP-27 and PRP combined with high pressure liquid chromatography that all three PACAP precursor-derived peptides are detectable in tissue extracts from various brain regions, the gastrointestinal tract, the urogenital tract and testes [13,14,22,23,25]. Surprisingly the not fully processed form of PACAP, PACAP-38, is the dominating peptide in all tissues examined. The tissue concentrations of PACAP-27 and PRP amount only 7–20 and 1–10% of that of PACAP-38, respectively [14,23]. By immunohistochemistry a complete co-localization of PRP and PACAP has been demonstrated in all PACAP containing cells examined so far (Fig. 2D–F) [25,49]. Whether this co-existence is of functional significance and whether PRP, PACAP-27 and PACAP-38 are co-released or
co-secreted remains to be solved. The effects of PACAP-38 and PACAP-27 are well described and are in most biological systems identical [73]. Our knowledge of PRP’s biological actions is, however, limited. A few studies have demonstrated that PRP has similar effects as PACAP but displays much lower potency, while the extended form of PRP, named big PRP, has limited biological actions [35,75].
5. Co-existence of VIP and PACAP, two structurally related peptides derived from separate precursors The distributions of VIP and PACAP in the central nervous system are substantially different and PACAP is much more widely distributed than VIP [7,20,39]. In the brain the two peptides have only been demonstrated to co-exist in a few cortical neurons [15]. In contrast to the central nervous system VIP and PACAP often appear to be co-localized in the same nerve cell bodies and nerve fibers in peripheral organs. In the mammalian gastrointestinal tract VIP
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Fig. 2. (A–C) Confocal photomicrograph showing co-localization of VIP (A) and PHI (B) (merged image C) in nerve cell bodies and fibers in a coronal section through rat suprachiasmatic nucleus. oc: optic chiasma. (D–F) Confocal photomicrograph showing co-localization of PACAP (D) and PRP (E) (merged image F) in nerve cell bodies and fibers in a coronal section of paraventricular nucleus from colchicine pretreated rat. 3v: third ventricle.
and PACAP are often found to be co-stored in nerve cell bodies and nerve fibers located in the myenteric and in the submucosal plexa of the small and large intestine (Fig. 4C and D) as well as in the myenteric cell bodies and fibers of the esophagus and gastric antrum [22,60,68]. In the gastrointestinal tract PACAP modulates motility and secretion, effects which exhibit a location-dependent variation [47]. Many of the actions are shared with VIP suggesting that the two peptides could be co-mediators. In addition VIP and PACAP are co-stored in neuroendocrine tumor cells [12] and in parasympathetic ganglia such as sphenopalatine, the otic, the jugular nodose, the ciliary and the submandibular ganglia [53,64] and in ganglia innervating the lung, the urogenital tract, the adrenals, the eye and in nerve fibers innervating the sweat glands [13,14,63,69,71]. Co-localization of VIP and PACAP is also seen in dorsal root ganglia after axotomy [79] and in the sympathetic superior cervical ganglion following preganglionic denervation [17]. In these ganglia the increase in PACAP expression after denervation is rapid and transient, while elevated VIP expression occurs much later suggesting the two peptides play a complementary functional role during neuronal regeneration. Since most target areas for VIP and PACAP express both the PACAP specific PAC1 receptor and the VIP/PACAP shared VPAC1 and VPAC2 receptors, detailed studies using receptor specific agonists and antagonists are necessary to clarify the
role of VIP and PACAP in the various parts of the nervous system.
6. Co-existence of VIP with the classical transmitter acetylcholine The evidence for co-localization of VIP and acetylcholine in a population of autonomic postganglionic neurons comes from studies demonstrating that the VIP immunoreactive cells contain high levels of acetylcholineesterase (Fig. 4A and B) [46] and the acetylcholine synthesizing enzyme, choline acetyltransferase [45]. Furthermore the ultra structural features of the VIP immunoreactive nerves have been shown to be similar to those of cholinergic nerves, i.e. a dominance of small clear vesicles (diameter ∼500 Å) which seem to store most of the acetylcholine and a few larger dense core vesicles (diameter ∼1000 Å) in which VIP is preferentially localized [42]. The immunoelectron microscopic studies have been supported by biochemical subcellular fractionation experiments which also disclosed that on a molar basis there are several hundred times as much acetylcholine as VIP [42]. The postganglionic parasympathetic nerves innervating blood vessels and exocrine elements of the cat submandibular gland have been used for functional analysis of the co-existence of VIP and acetylcholine [44]. Activation of these nerves causes salivary secretion and concomitant
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induce both salivation and vasodilation. At high frequency stimulation, however, the vasodilation is atropine-resistant, most likely mediated by the release of VIP. Although VIP is an atropine-resistant vasodilator in the submandibular gland the peptide does not alone provoke secretion. VIP can, however, potentiate the acetylcholine induced salivary secretion. Thus acetylcholine and VIP have complementary actions on the functional response in the salivary gland. For the secretory response acetylcholine acts as a neurotransmitter in the classical sense, while VIP serves as neuromodulator. In addition, both acetylcholine and VIP may be transmitters for the vasodilation. In vitro studies support an interaction between VIP and acetylcholine directly on the secretory cells since VIP in nanomolar concentrations can enhance the association rate of muscarinic ligand binding to membranes of the submandibular salivary gland [43]. Furthermore, carbachol enhances the cAMP formation induced by VIP which suggests interaction between acetylcholine and VIP at the second messenger level as well [16].
7. Co-existence of PACAP with the classical transmitter glutamate
Fig. 3. (A) Co-release of VIP and PHI during transmural electrical nerve stimulation (10 Hz, 2 ms, 150 mA for the period indicated by hatched bars) of smooth muscle strips from the corpus (upper panel) and antral part of the porcine stomach (lower panel). The peptide release was accompanied by a non-adrenergic, non-cholinergic smooth muscle relaxation. The solid line represents VIP immunoreactivity, the dashed line PHI immunoreactivity. (B) Dose–response curves for relaxant effects of VIP (䊉) and PHI () on spontaneous muscle activity of porcine gastric antrum in vitro. The effect is given as changes in amplitude expressed as the percentage of controls, i.e. no inhibition equals 0% and total relaxation equals 100%. Figures are given as the mean SEM of five experiments (from [9]).
increase in local blood flow. The nervous activation also causes an overflow of both acetylcholine and VIP into the venous effluent from the gland indicating co-release, and the VIP release is frequency-dependant being highest at high frequency stimulation. Both secretion and vasodilation are potentiated by inhibition of acetylcholineesterase and abolished by atropine at low frequency stimulation of the parasympathetic nerves supplying the submandibular gland. Thus acetylcholine is a prerequisite for salivation but could also be of importance for the increase in blood flow consistent with the finding that administration of acetylcholine can
The brain’s biological clock, which generates circadian rhythm of physiology and behavior, is as mentioned located in the suprachiasmatic nucleus [36]. The molecular machinery driving the circadian clock consists of a group of “clock genes” which in double autoregulatory feedback loops interact and control their own transcription within the neurons of the suprachiasmatic nucleus [61]. The clock is daily adjusted to the environmental light/dark cycle, but the mechanism by which external light modifies the activity of the neurons in the suprachiasmatic nucleus is still incompletely understood [61]. The light signaling pathway originates in a small population of retinal ganglion cells that project to the suprachiasmatic nucleus via the retino-hypothalamic tract [51]. These neurons are characterized by the expression of the circadian photopigment melanopsin [24] and co-store both the classical neurotransmitter glutamate and PACAP (Fig. 4E and F) [26]. Glutamate has for years been considered an important mediator of adjustment in circadian timing in response to light [8], but recent studies indicate that glutamate and PACAP both play a role in a rather complex functional interplay [19]. Thus PACAP in nanomolar concentrations can phase-shift the endogenous rhythm of the biological clock similar to light and glutamate whereas PACAP in micromolar concentrations modulates glutamate induced phase-shifting of the clock. Recent in vivo studies using a PAC1 receptor antagonist or mutant mice lacking the PAC1 receptor have shown that this receptor plays a role in modulating light induced resetting of circadian rhythm and light induced “clock gene” expression in the suprachiasmatic nucleus [1,21].
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Fig. 4. (A, B) Consecutive sections of cat submandibular ganglion immunostaining for VIP and stained for acetylcholineesterase (AchE) indicating that VIP and acetylcholine occur in the same neurons (kindly provided by J. Lundberg). (C, D) Double immunostaining of section of rat small intestine showing co-localization of PACAP and VIP in nerve cell body (large arrow) and fibers (small arrows) in the myenteric (mye) and submucosal plexa (sub). PACAP containing neuron lacking VIP, but innervated by VIP is indicated by arrowhead. (E, F) Double immunostaining of sagittal section of rat retina showing that PACAP is co-localized with glutamate in a subpopulation of ganglionic cells (large arrows) and their processes (small arrows). Abbreviations: GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; ONL, outer nuclear layer (from [26]).
8. Concluding remarks In the present paper we have presented a number of examples where neurons containing VIP or PACAP have been shown to contain another substance, possibly involved in the process of chemical transmission at synapses. The existence of multiple transmitters and their simultaneous or sequential release require multiple forms of recep-
tors on both postsynaptic and presynaptic membranes. A number of possibilities exist how the co-existing transmitters may work together and evoke diverse physiological responses: (1) Both transmitters may cross the synaptic cleft and exert their action via stimulation of either the same or different receptors on the postsynaptic cell.
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(2) One transmitter may activate receptors on the postsynaptic cells whereas the other transmitter blocks another type of receptor. (3) One transmitter may act on the postsynaptic cells whereas the other transmitter may exert its action on presynaptic autoreceptors. (4) One transmitter may act on the postsynaptic cell whereas the other transmitter may act on presynaptic receptors located on nerve endings of other neurons. (5) One transmitter may act on one cell type and the other transmitter on another cell type in the target organ. The mere demonstration that two transmitter substances are co-localized in the same neuron does, however, not necessarily mean that they function as co-transmitters. The substances must be demonstrated to be co-released during physiological activation of the neurons and exert pre- or postsynaptic actions. The co-localization of peptides in the same neuron which are synthesized from the same precursor could imply a functional role but some of the peptides may just represent inactive split products. Although the functional significance of the co-existence of peptides and classical neurotransmitters is not fully elucidated, it seems that the role of the peptide is to modify the effect caused by the classical transmitters. It is possible that a classical transmitter system can be subdivided on the basis of co-existence with specific peptides. The release of the peptide and classical transmitter upon nervous activation may depend on the intensity of stimulation (the peptide release requires a higher stimulation frequency) and often the peptide seems to be responsible for the component of the biological response characterized by slow onset and long duration. Future research will hopefully define more exactly the interactions between peptide and classical transmitter. Furthermore it will be relevant to analyze to what extent the balance among multiple synaptic transmitters is disturbed during various nervous disorders and how neuroactive drugs may affect the interplay of multiple transmitters.
Acknowledgments The study was supported by The Danish Biotechnology Center for Cellular Communication.
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