Tachykinin receptors in gastrointestinal motility

ELSEVIER

Regulatory Peptides 57 (1995) 19-42

Review

Tachykinin receptors in gastrointestinal motility Ulrike Holzer-Petsche* Department of Experimental and Clinical Pharmacology, Karl-Franzens-University, Universit~tsplatz 4, A-8010 Graz, Austria Received 14 February 1995; accepted 14 February 1995

Keywords: T a c h y k i n i n ; T a c h y k i n i n receptor; G a s t r o i n t e s t i n a l motility

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20

2. Overview on TKs and their precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20

3. TK receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Receptor subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Selective ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. ReceptoT heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. N K t-receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. NK:,-receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.3. NK:)-receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Molecular biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Effects on excitable membranes and transduction mechanisms . . . . . . . . . . . . . . . . . . . . . . . . .

21 21 21 22 22 23 23 24 24

4. TK receptor;~ in the gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Occurrence of TKs and their receptors; release of TKs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Functions in motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Guinea-pig . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.1. Isolated muscle strips . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.2. Intraspecies heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.3. Intestinal motor reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Rat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Dog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4. Cat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25 25 27 27 27 28 28 29 30 31

* Corresponding author. Abbreviations: SP, substance P; NKA, neurokinin A; NKB, neurokinin B; TK, tachykinin; NK, neurokinin; PPT, preprotachykinin; AER, ascending enteric reflex. 0167-0115/95/$9.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0 1 6 7 - 0 1 1 5 ( 9 5 ) 0 0 0 1 9 - 4

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

20

4.2.5. Human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.6. Other species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31 31

5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32

I. Introduction

of NKA, NKB, neuropeptide K, and neuropeptide

The TKs are a group of peptides widely occurring in mammalian and nonmammalian tissues. As early as in the first publication on SP, the first compound of this group discovered, its ability to contract the rabbit jejunum was studied [1]. Before the availability of a radioimmunoassay for SP this property was made use of in bioassays to measure the activity of SP-containing extracts. The TKs are phylogeneticaUy old peptides, SP-like immunoreactivity being found in species as low as Hydra [2]. For a long time SP was the only TK known to occur in mammals. Differences in potency between SP and nonmammalian TKs, notably eledoisin and kassinin, in many bioassays led researchers to hypothesize the existence of different binding sites and to the discovery

The present summary focusses on the role of TKs in gastrointestinal motility with particular emphasis on the distribution and involvement of specific TK receptors. In addition, the reader is referred to the review by Barth6 and Holzer [3] discussing data up to 1985, to the review on SP by Otsuka and Yoshioka [4], to Maggi et al. [5] and Mussap et al. [6] surveying aspects of TK receptors and their ligands, and to the comprehensive monograph on TK receptors by Buck [7]. 2. Overview on TKs and their precursors

The TKs are defined by their common C-terminus Phe-X-Gly-Leu-Met.NH 2. Those most important

Table 1 Amino acid sequence and receptor preference of tachykinins most important for research in mammals Substance P Neurokinin A Neurokinin B Neuropeptide K

Neuropeptide 7 Physalaemin Eledoisin Kassinin Scyliorhinin II

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met.NH2 His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met.NIt2 Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met.NH2 H-Asp-Ala-Asp-Ser-Ser-Ile-Glu-Lys-Gln-Val-Ala-Leu-Leu-Lys-Ala-Leu-Tyr-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Ph..~e-Val-Gly-Leu-Met.NH2 Asp-Ala-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met.NH2 pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Gly-Leu-Met.NH2 pGlu-Pro- Ser-Lys-Asp-Ala-Ph.._~Ile-Gly-Leu-Met.NH2 Asp-Val-Pro-Lys-Ser-Asp-Gln-Ph__~e-Val-Giy-Leu-Met.NH 2 S S

NK1 > NK2 > NK3> N K 2>

NK2 > NK3 NK3 > N K 1 >NK2~NKI N K t >> NK3

N K 2 > N K 1>> N K 3 N K 2> NK~ > NK3> N K 2>

N K 4 >> N K 3 N K 2> N K 3 >NK2~NK 1 N K l >> N K 3

I

Ser-Pro-Ser-Asn- Ser-Lys-Cys-Pro-Asp-Gly-Pro-Asp-Cys-Ph_.~e-Val-Gly-Leu-Met.NH2

NK3 > > NK1 >> NK2

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

for functional studies in mammals are listed in Table 1. The mammalian TKs are derived from larger precursor peptides, the PPTs, which in turn are encoded by two different PPT genes. The RNA derived from the PPT-A (or PPT-I) gene undergoes alternative splicing thereby yielding the mRNAs for three different precursor peptides: ~-PPT-A contains the sequence for SP only; from fl-PPT-A and ~-PPT-A both SP and NKA are derived as well as Nterminally extend,~d forms of NKA, namely N P K from fl-PPT-A and NP~ from ~-PPT-A [8]. A fourth form of PPT-A, 6-PPT-A, is produced in rat dorsal root ganglion cells and contains the sequence of SP and possibly of a 22 amino acid-C-terminal peptide unique to this fo~an of PPT [9]. The mRNA for 6-PPT-A also occurs in the intestine, but in lesser amounts than that for fl-PPT or ~-PPT mRNA [ 10]. The PPT-B (PPT.-II) gene encodes the sequence of a single PPT from which NKB is derived. In the enteric nervous system, the mRNAs for ~-PPT-A and fl-PPT-A prevail, whereas only little ~-PPT-A mRNA is found [ 11 ]. This implies that in practically all TKergic enteric neurons N K A coexists with SP.

21

SP, as was eledoisin to kassinin. Between the two groups, however, there were often differences in potencies [ 13]. A similar strategy led Lee et al. [ 14] to propose two different receptors for TKs, namely a SP-P receptor which preferentially recognizes SP and a SP-E receptor preferring eledoisin. These works stimulated the development of receptorselective ligands and even the discovery of new mammalian TKs, namely N K A and NKB [15-18]. A substance K (= NKA)-preferring receptor was first described by Buck etal. [19]. It has to be stressed in this context that all naturally occurring TKs act as full agonists on all types of TK receptor, and that it is only differences in potency that hinted at a diversity of the TK receptors. From 1984 on many researchers confirmed the notion of three receptor types for the TKs and characterized isolated organ preparations presenting with a single receptor type [20-23]. At the Montreal Meeting on Substance P and Neurokinins a nomenclature for the receptors was agreed upon, calling them NK1, NK2 and NK 3 [24]: the term NK 1 denotes what has previously been called SP-P or NK-P, NK 2 now stands for the SP-K or NK-A receptor, and NK 3 replaced the terms SP-E or NK-B.

3. TKreceptors 3.2. Selective ligands 3.1. Receptor subtypes

Contrary to the investigation of other transmitter receptors, the study of TK binding sites for many years relied exclus:ively on the comparison of potencies of agonists, most of them nonspecific ones, in various experimenlLal setups. Even with these limited means the existence of different types of binding sites was soon suspected. An early hypothesis was put forward by Piercey et al. [ 12] on the basis of different sensitivities o:r various preparations to C- or N-terminal fragments of SP. Another approach was made by comparing various nonmammalian TKs with SP in a range of bioassays, yielding two groups of peptides: physalaemin was always equipotent to

By modifying the amino acid sequence of the natural TKs various agonists were synthesized that proved selective for one of the TK receptor types (Table 2), A similar chemical approach was used for the first generation antagonists, which contain D-amino acids, such as [D-Pro2,D-Trp7'9]-SP [25] or spantide I [26]. Although most of them are reasonably specific at TK receptors, they are by no means receptor-selective and have other disadvantages such as neurotoxicity or a local anaesthetic action. A second step involved the development of more specific TK analogues, as well as of cyclic peptides or pseudopeptides as, e.g., M D L 28,564 [27] or MEN 10,573 [28]. The third generation an-

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

22 Table 2

Selective ligands for tachykinin receptors and monoreceptor assays Selective agonists NK 1 SP-methyl ester [227] [Sarg, Met(O2)ll]-sP [229] [Pro9]-SP [229] Septide [231]

Selective antagonists

Selective radioligands [6]

Monoreceptor assay

GR 82,334 [228] CP-99-,994 [30] RP 67580 [31] RPR100893 [232] SR 140333 [32]

125I-Bolton-Hunter[sarg,Met(O2)lt]-SP 3H-[Sar9,Met(O2)ll]-SP

dog carotid artery [22] rabbit vena cava [230]

NK2

[flAlaSI-NKA(4-10) [233] [Nlel°]-NKA(4-10) [229]

L 659,877 [234] R 396 (NK2a > NK2A) [62] MEN 10,376 (NK2A) [235] MEN 10,627 (NK2B) [64] MDL 28,564 [237] a SR 48968 [33]

125I-[LysS,Tyr(I2)7,MeLeu9, Nlel°]-NKA(4- 10) 125I-iodohistidyl-NKA

rabbit pulmonary artery (NK2A) [22] guinea-pig trachea (NK2A) [22] hamster trachea (NK2B) [236]

NK 3

Senktide [144] [MePheV]-NKB [229]

SR 142801 [34]

3H-Senktide 12SI-Bolton-HunterScyliorhinin II

rat portal vein [22]

a MDL 28,564 is a competitive antagonist on NK2B receptors but a weak partial agonist on NK2A receptors [237].

tagonists are represented by nonpeptide compounds such as CP-96,345 [29], CP-99,994 [30], RP 67580 [31], or the Sanofi compounds [32-34]. Whereas CP-96,345 has the drawback to block L-type Ca 2 ÷ channels in concentrations close to the ICs0 [35], much less of this effect is observed with SR 48968 and RP 67580 [36] and none with CP-99,994 [30,36]. Compared with other nonpeptide antagonists RP 67580 penetrates the blood brain-barrier only poorly, which allows to differentiate between central and peripheral effects [26]. A detailed discussion of receptor-selective radioligands was published by Mussap et al. [6].

3.3. Receptor heterogeneity The naturally occurring TKs show more or less the same affinity to their preferred receptors in the various species examined. Apparent differences in potency between tissues often are caused by different combinations of proteases which are responsible for individual breakdown patterns of released TKs [4,37,38]. However, with the development of recep-

tor-selective antagonists a considerable heterogeneity in the pharmacology of TKs was observed. This goes from differences in affinity in different species as far as to differences in the compound's principal effect, as is the case for M D L 28,564 (see Table 2).

3.3.1. NKl-receptor The development of nonpeptide NK1 antagonists brought the first pharmacological evidence for species-related variations of this receptor: the quinuclidine compound CP-96,345 was up to 100 times more potent in human, guinea-pig, rabbit, bovine, hamster, and gerbil tissue compared with rat and mouse, whereas the perhydroisoindole derivative RP 67580 showed the opposite preference [39-47]. Point mutation studies with human and rat NK~ receptors have shown that only few amino acid residues determine the affinity for a particular antagonist [48,49]. These crucial residues may differ for the various antagonists tested and need not even be directly involved in the binding but may induce allosteric effects [50,51 ]. Thus, it seems as if the distinc-

u. Holzer-Petsche/ Regulatory Peptides 57 (1995) 19-42

tive binding environment for each ligand must be determined in specific experiments. Contradicting lhadings exist as to a difference between central and peripheral NK 1 receptors within a single species. Comparison of the displacement of selective NK 1 agonists by various agonists and antagonists gave no indication as to intraspecies differences between central and peripheral NK 1 receptors [43,52,53]. In contrast, Lew et al. [54] reported that various ligands for TK receptors were more potent in displacing ~2SI-Bolton-Hunter[Sar9,Met(O2)ll]-SP from rat salivary glands than from rat brain tissue except for SP, [ Sar9,Met(Oz)! 1].Sp and physalaemin, which were equipotent in the two tissues. Similarly, CP-96,345 antagonized SP-methyl ester with greater potency in guinea-pig brain than in the ileum, however, RP 67580 showed no such distinction in corresponding tissues of the rat [55]. Another intraspecies heterogeneity of NKx receptors became apparent, when Petitet et al. observed a low affinity for septide on NK1 binding sites in the guinea-pig ileum, although septide was equipotent to [Pro9]-SP in NKL-mediated functional studies [56]. Structural considerations led these researchers to postulate a separate TK receptor sensitive to septide [57]. However, observations made on isolated cells with a single population of NK1 receptors led to the conclusion that septide bound to a different subsite on the NK 1 receptor than did SP [58,59]. 3.3.2. NK2-receptor

Maggi and coworkers [60,61] observed differences in the affinity of selective NK 2 antagonists to the corresponding receptors in rabbit and hamster tissue. Preparations from hamster and rat always differed from tho,~;e of guinea-pig, rabbit, bovine or human. On this basis Maggi proposed the existence of two subtypes of the NK z receptor: a NK2A receptor in guinea-pig, rabbit and human, and a NK2B receptor in rat and hamster with a possible further difference between the NK 2 receptors in the latter two tissues [62,63].

23

To date, only one copy of the gene encoding the NK 2 or, similarly, the NK~ receptor, has been identiffed in the various species examined. This supports the notion that the observed differences are species related variations rather than true receptor subtypes. However, the structure of these genes would allow for alternative splicing or posttranslational modification within a single species (for discussion see [64]). Supporting this notion are the experiments of Kage et al. [65] identifying two forms of the NK 1 receptor in rat submandibular gland, which differed in the length of their carboxy-termini. Thus, there is the possibility of slightly differing receptor proteins within a single species which might also underly some of the intraspecies variations observed in binding studies on NK 2 receptors of rat duodenum and urinary bladder [66]. 3.3.3. NK3-receptor

While there is no indication as to intraspecies variations of the NK 3 receptor [67], there do exist differences between species. The nonpeptide NK2antagonist SR 48968 displays moderate affinity for NK 3 receptors in guinea-pig and human tissue, though not in the rat [47,68-70]. This difference between the rat and the human NK 3 receptor was localized to only 2 amino acids of the receptor protein [71]. A species difference is also evident when agonists are used: NKB and [ProT]-NKB are more potent in displacing senktide from the rat than from the guinea-pig NK 3 receptor [68], and the binding affinities of various natural ligands to a cloned human NK 3 receptor differ from those to the rat receptor [72]. The new nonpeptide NK 3 antagonist, SR 142801, is more potent on NK 3 receptors in guinea-pig, gerbil and human brains than in rat brain [34]. In the rat portal vein, a typical NK 3 monoreceptor assay, SR 142801 is not very active [34] and displays a similar moderate affinity as on the rabbit NK 2 receptor [73].

24

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

3.4. Molecular biology

By now, the occurrence of three different types of TK receptors is well established. All three receptors have been cloned [74-76] (further references see [77]), and shown to belong to the superfamily of G-protein-coupled receptors with 7 transmembrane spanning domains, an extraceUular N-terminus, and an intracellular C-terminal segment. Typically for G-protein coupled receptors, the binding of agonists is modulated by guanine nucleotides, which, however, do not modify the binding of TK receptor antagonists [78]. The G-protein associated with TK receptors is insensitive to pertussis toxin [77]. For the TK receptor types identified so far in mammalian tissue there is a > 85Yo identity between species homologues, although much less homology exists between the different receptor types themselves [77]. The binding domains for the various ligands may differ in one and the same receptor. On human NK 1 receptors SP and NKB do not interact with the same set of functional groups [ 79]. Furthermore, the binding domain for agonists seems to differ from that of antagonists [ 80]. Most likely the antagonists, though behaving in a competitive fashion in pharmacological assays, do not displace the agonist from its binding site but lead to a conformational change of the receptor, thereby restricting the agonist's access to the receptor [81]. The ligand binding domain may also be distinct from the domain responsible for signal transduction [82]. Homologous domains on the NK 1 and NK z receptors expressed in Chinese hamster ovary cells seem not to be functionally equivalent, since exchange of these domains has no influence on binding affinities but prevents stimulation of phosphoinositide turnover [83]. 3.5. Effects on excitable membranes and transduction mechanisms

In neurons and smooth muscle the TKs induce a slow depolarization which in many instances leads

to action potentials (see [4,84]). The principal mechanism seems to be a decrease of the K +conductance, with an additional increase in C1-conductance (due to N K 1 receptors) contributing to the maintenance of the induced current [85-88]. Other mechanisms observed in intestinal smooth muscle include activation of voltage-sensitive Ca 2 +channels [85,88,89]; and also activation of Ca 2÷dependent K ÷ -channels [90]. Different TK receptor types may initiate different events in smooth muscle membranes even of the same species: in the circular muscle of guinea-pig colon the selective NK 1 agonist [Sar9]-SP induces depolarization and action potentials through nifedipine-sensitive CaZ+-channels, whereas in the same tissue the contraction in response to [flAla8]-NKA(4-10), a selective N K 2 agonist, depends on Ca 2 ÷ influx through receptorgated nonselective cation channels [89]. Contrary to these diversities, the second messenger system used by all three types of receptors is the same: binding of an agonist leads to activation of phospholipase C with the consecutive formation of inositol 1,4,5-trisphosphate and of diacyglycerol, which activates certain protein kinase C isoforms (see [91]). This pathway has also been confirmed for intestinal tissue [44,92-96]. The increase in phosphoinositides is not secondary to membrane depolarization but mediated directly by the binding of a TK agonist [97]. Both release from intracellular stores and influx through L-type channels have been shown to contribute to the TK-induced increase in intracellular Ca 2÷ mediated via inositol 1,4,5trisphosphate [85,98]. Two separate signalling mechanisms regulate the phasic and tonic components of the SP-induced contraction in the guineapig ileum longitudinal muscle: an increase in protein kinase C activity accelerates, and a decrease slows down, the fading of the tonic contraction without influencing the primary peak contraction [99]. In Chinese hamster ovary cells transfected with human ileal NK 2 receptors two distinct pathways, Ca 2÷ influx and protein kinase C activation, are necessary for NKA-induced prostaglandin release, and they

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

might even be regulated by different G proteins [ 100]. In submucous neurons of the guinea-pig caecum cAMP appears to mediate certain effects of SP [101]. In contra,;t, no production of cAMP by SP could be demons'trated in rat small intestine [93,96].

4. TK receptors in the gastrointestinal tract 4.1. Occurrence ~.1~ TKs and their receptors; release o f TKs

SP and NKA occur in the gastrointestinal tract of all mammals inw~,stigated so far. They are localized mainly in neurons intrinsic to the enteric nervous system and play a role not only in motility but also in secretion [ 102,103] and probably also as intrinsic sensory neurons [ 104]. In these intrinsic neurons, an intricate pattern of coexistence with amine transmitters and other neuropeptides has been revealed (see [105,106]). Small amounts of neuropeptide K have also been meast~red in the cat colon [107] and the circular muscle & h u m a n ileum [ 108] and neuropeptide ? has been identified in the rat gastrointestinal tract [109]. Neuropeptide K, however, is broken down to NKA during the packaging into synaptic vesicles [110] and is not itself released [107]. A minor contribution to the gastrointestinal TK content is made by primary afferents originating in the dorsal root ganglia or vagal nodose ganglia that reach the gastrointestinal tract via the mesenteric or paravascular nerves, the vagus or the sacral autonomic nerves (see [105]). The proportion of TKs from this source is somewhat higher in cat and dog [111-113] than in rat and guinea-pig [114,115]. In these extrinsic nerves the TKs coexist with calcitonin gene-related peptide [ 116]. For SP, there exists a third source, namely the enterochromattin cells of the small intestine. This localization appears to be less important in human than in other species [ 117,118 ]. Up to now, no NKB or the PPT-B mRNA has been located to the gastrointestinal tract

25

[110,119-121] (but see [122]); although in guineapig and rat NK 3 receptors have been identified in the gut [67,123,124] and seem to be involved in TKergic transmission. The cell bodies of the intrinsic TKergic neurons lie in the myenteric and submucous plexuses. Myenteric TKergic neurons innervate both the longitudinal and circular muscle [125], but they also play an important role as interneurons within the enteric nervous system, projecting to both myenteric and submucous neurons. From studies in the guinea-pig small intestine we know that the TKs in myenteric neurons mostly coexist with acetylcholine [ 126] and to a minor extent also with opioid peptides. Most of them, interneurons as as well as motoneurons, project orally before contacting their target cells [ 127,128]. In the rat jejunum, however, SP-fibres project anally to the circular and longitudinal muscles [ 129] but have ascending projections in the colon [ 130]. The occurrence of the TK peptides relevant to gastrointestinal motility is paralleled by the localization of TK receptors as outlined in Table 3 and summarized in Fig. 1. A recent autoradiographic study provided direct evidence for SP-immunoreactive nerve fibres contacting NKl-positive enteric neurons or circular muscle cells in rat intestine [131]. The release of SP and NKA from intestinal tissue has been measured directly as a prerequisite for a physiological role of these peptides. Electrical field stimulation, increase in K ÷ concentration, but also acetylcholine and other mediators, have been shown to modulate the concentration of SP and NKA in the superfusion medium or the venous outflow as measured by radioimmunoassay [ 132-135]. Physiological stimuli such as distension-induced peristalsis or reflex activation of the pelvic nerves by rectal distension also cause release of SP and NKA, but not neuropeptide K, concomitant with contractions of the intestine [96,136,137].

Humanc

Cat

Dog

Rat

NKI: CM, LM, LOS [203]

neuronal effects

motility

binding studies

neuronal effects

motility

NKI: CM [215] NKI: antrum only [215] NK2: CM [215] NK2: CM, LM [215] NKI: CM [210] NK2: CM, LOS [210,2111 NK1 [215]

NKI [190]

NKl: CM, LM [203]

NK 1 [190,192] NK 3 [192]

neuronal effects binding studies

NKI: CM [192]

NK2: CM [192,250]

NKI: CM [250]

NK 1 [131]

NK2: CM, LM [174,175,176] NK3: LM [176]

NKI: CM, LM [175,239] NK2: CM [175]

motility

binding studies

neuronal effects

binding studies, receptor immunohistochemistry motility studies

NKI, NK3 [159,160]

neuronal effectsb

Stomach

NKb NK2: CM [159]

NKI: musc. externa [247]

Oesophagus

motility studies

Guinea-pig binding studies

Species

NK3 [245]

NKI: CM, LM [203]

NKI: sphincter [2501 NK2: sphincter, CM [250] NKI: sphincter [192] NK2: CM [192] NK 1 [192]

NKI: taenia, CM [97,156,161] NK2: CM [156,161]

NKI: CM, LM [238,239]

Colon

NKI: CM, LM [193,194] NK2: CM [193] NK 1 [194,250] NK2 [2501

NKI: CM [192]

NKI: CM [215] NKI: CM [215] NK2: CM, LM [215] NK2: CM, LM [215] NKI: CM [108,214] NK2: CM, LM [16,108,213,214]

NK1 [251]

NKI: CM, LM [203] NKI: CM, LM [203]

NKI: CM [215,216] NK2: CM, LM [215] NK2: CM [16,217]

NKI: CM [204,251] NK2: CM [204] NK b NK 2 [204,251]

NKI: CM, LM [203]

NK l [250]

NK2: CM [250]

NK2: CM [250]

NK2: CM [250]

NK 1 [192,250] NK3 [192]

NKI: CM, LM [250]

NK 1 [131,204,239] NK 2, NK 3 [204]

NK b NK 2, NK3: CM [2041

NK2: CM, LM [247]

NKI: CM, LM [239,247]

NKI: CM, LM [250] NKI: CM, LM [250]

NKI: LM [177,178] NK1, NK2, NK3: LM [96,181] NK2: LM [177,178,179,246] NK3: LM [179] NKI [239] NK 1 [131]

NKI: CM [131]

NK3: taenia [97] NKI [56,148,163,244,246] NKI [239] NK 3 [34,67,124,145,146, NK 3 [158] 148,149,179,243,244,246]

NKI: CM, LM [52,238,239,240,241] NK2: CM, LM [242] NKI: CM, LM [148,161,179,243,244] NK2: CM [139,148,149,161]

NKI:LM, CM [238,239] NK b NK2: CM a

Jejunum/ileum

Duodenum

NKI: CM [239] NK2: CM, LM [242,248,249]

Pylorus

Distribution of T K receptors involved in regulation of gastrointestinal motility

Table 3

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U. Holzer-Petsche I Regulatory Peptides 57 (1995) 19-42

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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fig. 1. Schematicdrawing of TKergicneurons and TK receptors involved in the regulation of ileal motility in the guinea-pig. LM, longitudinal muscle; NiP, myentericplexus; CM, circular muscle; DRG, dorsal root ganglion; NK1, NK2, NK3,TK receptor types; M, muscarinic receptor; N, nicotinic receptor; CGRP, calcitonin gene-relatedpeptide. [], neuron containing TKs (SP + NKA) but no acetylcholine; ©, neuron containing TKs + acetylcholine;C>, neuron containing acetylcholinebut no TKs; z~,neuron containing nitric oxide synth~tse. 4.2. Motility 4.2.1. Guinea-pig 4.2.1.1. lsolated muscle strips. For a long time, the direct stimulation of guinea-pig ileum longitudinal muscle was thought of as being mediated by a N K 1 receptor only (see [3]). Jacoby et al. [ 138], by comparing the effects of the mammalian T K s and first generation antagonists, already suggested the contribution of N K 2 receptors. This was later confirmed by the use of selective ligands [22]. Also in the circular muscle of the guinea-pig ileum the contribution of N K 2 receptors to TK-induced contractions was confirmed [139,1,10], the order of potency of the N K 2 antagonists used indicating the NK2A receptor

27

subtype [5,139]. Experiments with isolated cells from circular or longitudinal muscle, however, yielded contradicting results: the isolated cells were much more sensitive to the action of TKs than a strip of whole muscle, but they seemed to exhibit only a single type of binding site with the rather unusual order of potency of physalaemin = N K B > S P > N K A [ 141]. Barth6 et al. [ 142] reported differences in the ability of SP to stimulate atropine-resistant and atropinesensitive contractions of the guinea-pig ileum longitudinal muscle. It was basically the development of senktide that enabled the distinction between a N K 1 receptor on the longitudinal muscle mediating the atropine-resistant contraction and a N K 3 receptor on cholinergic interneurons responsible for the atropine-sensitive component of SP's effect [138,143,144]. Moreover, N K 3 receptors also reside on SP-containing motoneurons to the longitudinal muscle [ 145] and thus senktide contracts the longitudinal muscle via release of both acetylcholine and SP. The release of acetylcholine by N K B or senktide involves the activation of N-type voltage-sensitive Ca 2 + -channels [ 146] and is reduced in the presence of a lipoxygenase inhibitor, demonstrating a facilitatory influence of arachidonic acid derivatives [147]. In the circular muscle activation of N K 3 receptors also induces contractions which are partly atropine-sensitive [148]. In addition, however, senktide triggers an inhibitory pathway [ 149] which finally leads to relaxation of the circular muscle via nitric oxide [ 150]. In vivo, the TKs that induce contractions of the guinea-pig ileum need not only be derived from intrinsic neurons. Stimulation of afferent nerve endings by capsaicin, or electrical stimulation of mesen-

CM, circular muscle; ]LM,longitudinal muscle; LOS, lower oesophageal sphincter. a C.A.Maggi, personal communication b Neuronal effects include changes in electrical properties of, and release of mediators from, enteric neurons as well as indirect effects on motility. c No evidence has been found for NK~ receptors in the human gastrointestinal tract [210,211,214,215].

28

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

teric nerves also lead to contractions of guinea-pig ileum smooth muscle [ 151,152]. In the longitudinal muscle this contraction is partly brought about by an action of SP on the smooth muscle itself, partly via activation of cholinergic intrinsic neurons [ 151 ]. The circular muscle, however, is not directly activated by TKs released from primary afferents. They rather seem to stimulate intrinsic neurons via N K 3 and possibly also via receptors for calcitonin gene-related peptide. Consequently these enteric motoneurons activate the circular muscle via both NK~ and N K 2 receptors [73,153]. The contribution of all three receptor types to contraction of the guinea-pig ileum circular muscle has been summarized by Maggi et al. [ 148] with the help of selective agonists: NKI receptors mediate an atropine-resistant, but partly TTX-sensitive contraction, N K 2 receptors are localized exclusively on the smooth muscle and N K 3 receptors exclusively on neurons, part of which use transmitters other than acetylcholine. In the guinea-pig taenia coli, both SP and N K A have been proposed as transmitter candidates [ 154]. The receptors mediating contraction of the proximal colon longitudinal muscle and taenia caeci seem to be predominantly of the NK~ type located on the smooth muscle with a minor contribution of N K 3 receptors [97,155]. In the circular muscle, however, N K 2 receptors and N K 1 receptors comediate nonadrenergic, non-cholinergic contractions. In this preparation N K 1 receptors mediate a fast transmission which depends on voltage-sensitive Ca 2÷ channels sensitive to nifedipine, whereas activation of N K 2 receptors initiates a slower type of transmission independent of such Ca 2 ÷ -channels [ 156]. No difference was observed in studies on duodenal circular muscle, where N K 1 and N K 2 receptors cooperated in non-adrenergic, non-cholinergic excitation and were both coupled to nifedipine-sensitive Ca 2 ÷ channels (C.A. Maggi, personal communication). In the colon, there are additional NK~ receptors on intramural T K neurons which contribute to the excitation of the circular muscle [ 157]. As in the ileum,

a neuronal N K 3 receptor mediates non-adrenergic, non-cholinergic relaxations of the colon circular muscle via release of nitric oxide [ 158]. All three receptors types occur also in the guineapig stomach. Functional experiments revealed the presence of N K 1 and N K 3 receptors on intrinsic neurons mediating relaxation via the release of vasoactive intestinal polypeptide and nitric oxide. Contraction of the smooth muscle is brought about via N K 1 and NK2 receptors [ 159]. In contrast, intracellular recording of myenteric neurons of the gastric corpus revealed only the presence of N K 3 receptors [ 160].

4.2.1.2. Intraspecies heterogeneity. Different potencies of septide and other selective N K 1 agonists were observed in binding and functional studies in the guinea-pig ileum and-colon [56,161]. The nonpeptide NK~ antagonist CP-96,345 inhibited septide with an affinity about 10 times higher than it did [Sar9]-SP sulfone [162]. Recently, Burcher etal. [ 163] localized a septide-sensitive receptor to inhibitory intrinsic neurons, since longitudinal muscle contractions in response to septide were increased by TTX. As already mentioned earlier, these differences are more likely to be due to a distinct binding epitope on the N K 1 receptor for septide than due to the existence of intraspecies receptor subtypes [58,59]. There is also evidence for differences in the N K 2 receptors in ileum and colon circular muscle [161]: whereas in both regions NKl-mediated contractions are sensitive to nifedipine, this is the case for N K 2mediated effects only in the ileum. Moreover, of the N K 2 antagonists tested, SR 48,968 is a competitive antagonist in the colon but noncompetitive in the ileum, and M E N 10,376, being a competitive antagonist in both regions, is more potent in the colon. The significance of these findings certainly needs further investigation. 4.2.1.3. Intestinal motor reflexes. The peristaltic activity is composed of two major components: an

u. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

ascending contraction and a descending relaxation. Both components are mediated by distensionsensitive sensory neurons, interneurons and motoneurons [ 127]. The involvement of endogenous SP in the peristaltic activity of the guinea-pig ileum has been well established (see [3]) as has been the dependence of the ascending component on TKergic transmission both in the ileum and in the colon [127,128,164,165]. In isolated guinea-pig ileum distension-induced peristalsis as well as the AER is mediated predominantly by both acetylcholine and TKs, because atropine and TK antagonists each reduce reflex contractions and only together lead to a complete blockade [165,166]. A second cholinergic pathway using nicotinic receptors in neuroneuronal transmission seems to be activated in parallel with the muscarinic one [ 165,167]. Only during the last years, however, the role of the various TK receptor types in peristalsis and the AER has been investigated in detail. Holzer et al. [ 128] observed that not only the size of the reflex con'traction in the AER but also the propagation velocity was inhibited differently by the nonselective antagonist spantide and the NK 2selective antagonist MEN 10,376, and that selective NK 1 receptor blockade had no effect. Further investigation together with the information from studies on isolated st:rips as outlined above yielded the following picture: NK 2 receptors play a major role in neuromuscular transmission to the circular muscle during the AER [128,139,168]. Maggi et al. [168] were also able to detect a N K 1 component in addition to the NK 2 effect. This NK 1 component, however, was less important in the distension-induced AER than in the AER evoked by electrical field stimulation. Similar findings were obtained in the colon of anaesthetized animals [ 169]. However, TK receptors must also be involved in neuroneuronal transmission, because spantide reduced the oral propagation of the reflex contraction, an action that was not paralleled by a specific NK 1 or N K 2 antagonist [128]. Most likely this effect of spantide reflects the blockade of NK 3 receptors on cholin-

29

ergic motoneurons. Recently, Maggi et al. [ 168] observed that a combination of NK1 and NK 2 receptor blockade was not able to abolish the atropineresistant AER evoked by either distension or electrical field stimulation. These authors therefore postulated the existence of a third neuromuscular transmitter beside acetylcholine and TKs. Also in experiments measuring distension-induced peristalsis evidence for muscular NK 2 receptors has been found [170]. Surprisingly, however, SP first stimulated, then inhibited peristalsis, stimulation of NKa receptors with SP-methyl ester solely inhibited, and the selective NK 3 agonists senktide facilitated atropine-sensitive peristaltic contractions [ 170,171 ]. Therefore, all three TK receptors may play a role in the mediation of peristaltic contractions in the guinea-pig small intestine. Divergent observations were published about a differential involvement of the atropine-sensitive and the atropine-resistant pathway in the AER or in peristalsis. Low diameter distension or low intraluminal pressure stimulated preferentially the atropinesenstive part, whereas a stronger stimulus was needed to induce the atropine-resistant activity [128,139,169]. In studies on isolated colon circular muscle, however, no difference was found in the stimulation parameters necessary to induce cholinergic or TKergic contractions [172]. 4.2.2. R a t

In the rat, the TKs induce only contraction of gastrointestinal smooth muscle via all three receptor types. It is mainly NK 2 receptors that mediate the contractions of the gastric fundus [ 173 ] and corpus [ 174], although there is also evidence for a minor amount of NK 1 and N K 3 sites on the circular [175] and for NK 3 sites on the longitudinal muscle of the fundus [ 176]. As has been discussed above, the NK 2 receptors in the rat are of the NK2B subtype according to Maggi [28,62]. In the duodenum of anaesthetized rats, the participation of NK~ receptors in the phasic and of NK 2 receptors in the tonic contractions in response to

30

U. Holzer-Petsche / Regulatory Peptides 57 (1995) 19-42

intravenously administered TKs has already been inferred from the order of potencies of natural agonists [177,178]. The development of senktide enabled Laufer et al. [ 179] to identify also a N K 3 receptor in the rat duodenum. The most potent T K on rat duodenum, however, is neuropeptide ),. It is 8-times as potent as [Nlel°]-NKA(4-10) and therefore Rahman et al. [180] postulated the occurrence of a different type of NK2 binding site or the action of neuropeptide V via N K 3 receptors. Although Sternini et al. [ 120] denied the existence of N K 3 receptors in the rat gastrointestinal tract, HellstrOm et al. [96] measured contractions of isolated intestinal smooth muscle cells in response to selective agonists to all three types of T K receptor. With the use of the NKI agonist [flAla4,Sar9,Met(O2)]-SP(4-11)and the N K 3 agonist [flAsp4,MePhe7]-NKB(4-1 l) Willis et al. [ 181] localized both receptors to ileal longitudinal muscle. As in the duodenum, there was a qualitative difference in the action of the two agonists: stimulation of the NK~ receptors led to tonic contractions, whereas the N K 3 receptors mediated phasic contractions. Discrepant results were reported about the influence on intestinal transit by TKs in conscious rats. Chang et al. [182] observed an enhancement of charcoal transit by septide but an inhibition by [ Nle lo ]_NKA(4_ 10) and senktide, although the total length of intestine was shortened after all agonists. In contrast, Tramontana et al. [183] saw a significant and specific enhancement of transit by [flAla8] NKA(4-10). In the colon, the muscularis muosae is contracted by TKs only via N K 2 receptors [184]. Grider et al. [ 164] demonstrated that, similar to the guinea-pig ileum, the ascending component of the peristaltic reflex in the rat colon is mediated by TKs and acetylcholine and that both SP and NKA seem to participate in the reflex contraction elicited by high grades of stretch. Both neuronal and muscular T K binding sites are involved, but no further attempt was made to characterize the T K receptor types. Again, similar to the guinea-pig, Scheurer et al. [ 185]

were able to unmask an inhibitory action of SP mediated by nitric oxide in rat colon. Also in the rat gastrointestinal tract, contractions induced by stimulation of primary afferent nerve endings by capsalcin are mediated by TKs [ 151,186].

4.2.3. Dog Although a number of data exist about the action of TKs in the dog gastrointestinal tract, few studies were performed with ligands selective enough to identify the types of T K receptors involved. In the antrum, SP was observed to increase the frequency of spontaneous phasic contractions. In the circular muscle layer, the site of action was on the smooth muscle, whereas the effect of SP on the longitudinal muscle was partly sensitive to TTX and atropine [187]. Earlier studies with a range of natural agonists suggested the presence of NK~ receptors responsible for atropine-sensitive contractions of the smooth muscle [188]. Strangely enough, they were not inhibited by spantide, but mimicked by splanchnic nerve stimulation [ 189]. Later it was shown that N K 1 receptors also initiate inhibitory mechanisms: SP-methyl ester selectively induced release of vasoactive intestinal polypeptide and prostaglandin E 1 from myenteric neurons and thereby reduced neuronal acetylcholine release [190]. In the lower oesophageal sphincter, studies with the mammalian TKs suggested both NK~ and N K 2 receptors to be involved in contraction, with N K 1 receptors being located on cholinergic neurons and NKz receptors on the smooth muscle [191]. Allescher et al. [192] investigated T K receptors in the pyloric region of anaesthetized dogs in more detail and located NK1 receptors on both neuronal and nonneuronal sites in antrum, pylorus and duodenum, N K 2 receptors to the smooth muscle of antrum and pylorus, and N K 3 receptors on neurons in antrum and duodenum. In vitro, however, only the NKx and N K 2 receptors on the smooth muscle could be identified [192]. In the ileum of anaesthetized dogs, TKs induce contractions via both N K 1 and NK2 receptors [ 193 ]. However, picomolar amounts of SP relax the ileum

U. Holzer-Petsche/ Regulatory Peptides 57 (1995) 19-42

via N K 1 receptors on cholinergic neurons, acetylcholine in turn acting on M-autoreceptors. Only concentrations :> 10-lo M SP induce atropinesensitive, even higher concentrations atropine-resistant contractions [ 194]. Similar effects of SP were observed in the colon, although no attempt was made to define the type of receptor involved [ 195,196]. 4.2.4. Cat

Many reseachers have demonstrated that SP contracts the gastrointestinal tract of cats in a partly atropine-sensitiw~ manner and that TKs are involved in motor reflexes [ 197] or in contractions induced by nerve stimulation [198-201]. N K A is more potent than SP in contracting the colon, and a release of both N K A and SP occurs into the blood during contractions [ 10],202]. Rothstein et al. [203] finally demonstrated binding of 125I-Bolton-Hunter-SP to NK~ sites in the cat gastrointestinal tract with a higher densitiy of binding sites over the circular than over the longitudinal muscle. From functional studies on colonic circular muscle Chang et al. [204] inferred the existence of both N K 1 and N K 2 receptors. 4.2.5. Human

Substance P, N K A and NKB have been shown to occur in the human gastrointestinal tract [118,205-209]. In the oesophagus and the lower oesophageal sphincter TK-induced contractions of the circular muscle are mediated exclusively by N K 2 receptors [210,211]. As in rats and guinea-pigs, SP and N K A are involved in the ascending contraction in human intestine [212]. The group of Maggi defined the role of T K receptors in the isolated human ileum by the use of receptor-selective agonists and antagonists [ 108,213,214]: the longitudinal muscle is contracted exclusively via N K 2 receptors, whereas the circular musclLe is excited via both N K 1 and N K 2 receptors located on the smooth muscle. These were further characterized as NKzA. Both preparations were insensitive to [MePhe7]-NKB, negating the presence of N K 3 receptors. These functional studies

31

correspond exactly to the autoradiography data of Gates et al. [215]. Also in the colon, [125I]-SP binding sites occur over the smooth muscle layers [216]. In functional studies only NK2A receptors could be localized to the circular muscle of the colon, and selective NKI and NK3 agonists were inactive [217]. K61bel et al. [218] observed a proximal to distal gradient for the response to N K A in the large intesfine. These NK2-mediated contractions were partly atropine-sensitive. A role of NK~ receptors was considered unlikely, because SP-methyl ester showed only little activity. However, atropine-resistant offresponses after electrical field stimulation were increased after desensitization to NKA, pointing to an additional presynaptic localization of N K 2 receptors, As in guinea-pigs and rats, SP and N K A from extrinsic, primary afferent, nerves can contribute to contracting the human jejunum as has been shown by the use of capsaicin [219]. In contrast, capsaicin only relaxes the huma taenia coli and there is no evidence for a participation of TKs [220]. 4.2.6. Other species

In rabbits, both N K 1 and N K 2 receptors have been localized to the gastric smooth muscle. Interestingly, the N K 1 receptors disappear with age, and in 11-week-old rabbits SP is two times less potent than at birth [221 ]. In the colon longitudinal muscle, the sensitivity to SP increases from proximal to distal, and the myogenic contraction is brought about by NK1 receptors [222]. In the distal colon there is also an atropine-sensitive component of the NK~mediated contraction. In the circular muscle, in contrast, SP, NKA, and NKB have the same potency throughout the length of the colon and their effect is brought about solely via smooth muscle receptors [222]. In the rabbit colon, extrinsic SP can also contribute to contractions of the longitudinal muscle

[223]. Two binding sites on smooth muscle are responsible for the TK-evoked contraction of mouse isolated distal colon. There is a NK~ site, whose acti-

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U. Holzer-Petsehe / Regulatory Peptides 57 (1995) 19-42

vation results in nifedipine-sensitive Ca2+-influx, and a second site, through which eledoisin and kassinin initiate nifedipine-insensitive contractions [224]. In the ferret, SP first contracts and then profoundly relaxes the lower oesophageal sphincter via NK 1 receptors, and this mechanism also takes part in the reflex relaxation of the lower oesophageal sphincter to oesophageal acidification [225]. In the sheep small intestine NK 1 binding sites on the smooth muscle have been identified [226] but not yet associated with a particular effect on motility.

5. Summary For a long time research on the action of TKs on gastrointestinal tissue has been demonstrating the importance of the TKs as non-cholinergic stimulators of motility in most parts of the mammalian gastrointestinal tract. The past years witnessed the development of TK agonists and antagonists selective for the various receptor types, which prompted a wealth of new insight into the pharmacology and molecular biology of the TK receptors. This knowledge now allows a more specific elucidation of the role of TKs and their receptors in the various aspects of gastrointestinal motility, not only in normal tissue but also under pathological conditions.

Acknowledgement Thanks are due to Dr. P. Holzer for critically reading the manuscript.

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34

[ 38]

[ 39]

[ 40]

[ 41]

[ 42]

[ 43]

[ 44]

[ 45]

[ 46]

[ 47]

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