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Tachykinin Receptors and Gastrointestinal Motility: Focus on Humans

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Tachykinin Receptors and Gastrointestinal Motility: Focus on Humans European Review for Medical and Pharmacological Sciences 2008; 12(Suppl 1): 69-80 Tachykinin receptors and gastrointestinal motility: focus on humans A. LECCI, M. ALTAMURA, A. CAPRIATI, C.A. MAGGI Clinical Research Department, Menarini Ricerche, Florence (Italy) Abstract. – Peptides of the tachykinin (TK) thors observed that this extract had myotropic ac- family were first discovered in the gastrointesti- tivity on isolated intestinal segments and postu- nal tissue about 75 years ago and supposed to lated that SP (P means powder, the physical form be involved in gastrointestinal (GI) motility. This of the extract) was released in the intestine and hypothesis has been repeatedly proven, al- though the role of TKs on motility is modulatory was the mediator responsible for its movements. rather than pivotal. Furthermore, beyond the well This hypothesis was verified 50 years later when known excitatory role, it has been acknowledged it became evident that TKs were, together with that TKs can also inhibit GI motility. TKs act at 3 acetylcholine, the main excitatory transmitters to 1 receptors termed as TK NK1 (NK1r), NK2 (NK2r), the gastrointestinal (GI) smooth muscle . During and NK3 (NK3r) receptors. The view gained the course of these 50 years the TK family en- through intense preclinical research suggested that motor effects induced by the stimulation of larged. Erspamer discovered, characterized and sequenced from non-mammalian species pep- NK2r were prominently mediated by a direct ac- tion on smooth muscle, those produced by the tides with SP-like biological activity which were 2 stimulation of NK1r were due to both muscular named tachykinins , i.e, fast relaxants of vascular and neuronal effects, whereas the motor effects smooth muscle, which were later shown to have 3 induced by NK3r were exclusively mediated by sequence homology to SP . In the early 1980s, neuronal effects. Recent functional and anatomi- three independent groups discovered novel mam- cal findings in humans are challenging this con- cept since NK r have been found in several kinds malian TKs which were named neurokinin A 2 (NKA) and B (NKB), and soon after elongated of myenteric neurons and selective NK2r antago- nists can, in particular conditions, produce GI forms of NKA were described (neuropeptide- motor effects likely related to a neuronal site of kappa and -gamma). At the eve of the new mil- action. Furthermore, the evidence for a myotrop- lennium, novel mammalian TKs were identified: ic role of NK1r is scarce, and very few studies, if hemokinin-1 (HK-1) and its elongated forms en- any, have documented a functional role for NK3r. 4,5 The findings that an acute or a long lasting dokinin A and B (Table I). TKs must share the common amidated C-ter- blockade of NK2r does not alter normal GI func- tions and that these receptors can modulate vis- minal motif Phe-X-Gly-Leu-Met-NH2 (were X ceral sensitivity are good starting points for test- has to be a non-polar amino acid) to exert biolog- ing this class of drugs in GI diseases charac- ical functions through TK receptors5-7 which terised by altered GI motility. have been termed NK1 (NK1r), NK2 (NK2r), and NK3 receptors (NK3r) (Table I). N-terminal SP Key Words: metabolites, such as SP1-5, also exert biological Clinical studies, Aprepitant, Nepadutant, Talnetant. effects, although these effects are not mediated by TK receptors but could involve a site regulat- ing the expression of delta opioid receptors8. TKs are encoded by 3 genes termed TAC1 (SP, NKA, neuropeptide-gamma and -kappa), TAC3 Introduction (NKB), and TAC4 (HK-1, endokinin A, B, C, and D) and each of these genes produces multi- Substance P (SP), the most famous component ple mRNA isoforms. Thus, both the beta- and of the tachykinin (TK) peptide family, was first gamma-TAC1 mRNAs produce both SP and extracted from the horse brain and intestine by NKA, whereas both alpha- and delta-TAC1 only von Euler and Gaddum in 1931. The same au- encode SP. Corresponding Author: Alessandro Lecci, BS; e-mail: [email protected] 69 A. Lecci, M. Altamura, A. Capriati, C.A. Maggi Table I. Amino acid sequence of tachykinins and tachykinin-related peptides and their receptor preference. In bold, the com- mon C-terminal sequence. Receptor preference has been assessed in functional experiments on Ca2+ mobilization or luciferase 5-7 assay (both responses are dependent on phospholipase C activation) in cells expressing human NK1 NK2 NK3 receptors . Peptides Amino acid sequence Receptor preference Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 NK1 > NK3 > NK2 Neurokinin A His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 NK2 > NK1 > NK3 Neuropeptide-gamma Asp-Ala-Gly-His-Gly-Gln-Ile-Ser-His-Lys-Arg-His- Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 NK2 > NK1 > NK3 Neuropeptide-kappa Asp-Ala-Asp-Ser-Ser-Ile-Glu-Lys-Gln-Val-Ala- NK2 > NK1 > NK3 Leu-Leu-Lys-Ala-Leu-Tyr-Gly-His-Gly-Gln-Ile- Ser-His-Lys-Arg-His-Lys-Thr-Asp-Ser-Phe-Val- Gly-Leu-Met-NH2 Neurokinin B Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2 NK3 > NK2 > NK1 Hemokinin-1 Thr-Gly-Lys-Ala-Ser-Gln-Phe-Phe-Gly-Leu-Met-NH2 NK1 > NK3 > NK2 Endokinin A Asp-Gly-Gly-Glu-Glu-Gln-Thr-Leu-Ser-Thr-Glu-Ala- Glu-Thr-Trp-Val-Ile-Val-Ala-Leu-Glu-Glu-Gly-Ala- Gly-Pro-Ser-Ile-Gln-Leu-Gln-Leu-Gln-Glu-Val-Lys- Thr-Gly-Lys-Ala-Ser-Gln-Phe-Phe-Gly-Leu-Met-NH2 NK1 > NK3 > NK2 Endokinin B Asp-Gly-Gly-Glu-Glu-Gln-Thr-Leu-Ser-Thr-Glu- Ala-Glu-Thr-Trp-Glu-Gly-Ala-Gly-Pro-Ser-Ile-Gln- NK1 > NK3 > NK2 Leu-Gln-Leu-Gln-Glu-Val-Lys-Thr-Gly-Lys-Ala-Ser- Gln-Phe-Phe-Gly-Leu-Met-NH2 Endokinin C Lys-Lys-Ala-Tyr-Gln-Leu-Glu-His-Thr-Phe-Gln-Gly-Leu-Leu-NH2 Antagonist at NK1 Endokinin D Val-Gly-Ala-Tyr-Gln-Leu-Glu-His-Thr-Phe-Gln-Gly-Leu-Leu-NH2 Antagonist at NK1 Hemokinin-1* Arg-Ser-Arg-Thr-Arg-Gln-Phe-Tyr-Gly-Leu-Met-NH2 NK1 > NK2 > NK3 *Rat and mouse sequence. TK receptors belong to class 1 (rhodopsin- of GI function such as immune-inflammatory like) seven transmembrane G-protein-coupled re- processes, tissue integrity, intestinal barrier func- ceptors. All tachykinin receptors can activate tion, carcinogenesis, blood supply, secretion, af- classical transduction mechanisms linked to ferent signaling and motor regulation. Although phospholipase C activation, and all natural TKs all these aspects can influence each other, this ar- having the common C-terminal sequence act as ticle is focussed on the role of TKs and their re- full agonists on these pathways, whereas their in- ceptors on GI motor regulation exerted at the pe- trinsic activity can vary when measured on other ripheral level with particular emphasis on evi- G-protein mediated pathways (e.g., increase of dence collected in humans. In this respect, it is cyclic adenosine monophosphate). TKs can also worth noting that TKs can also modulate GI exert biological effects through non G-protein motility by acting at sites located in the central mediated mechanisms (e.g., sustained activation nervous system, as it occurs for the anti-emetic of mitogen-activated kinases) but the agonist or- action produced by blood-brain barrier-penetrat- der of potency or intrinsic activity is unknown ing NK1r antagonists. for this transduction pathway9. Interestingly, en- dokinin C and D, which have been termed as TK-related peptides because both of them have a Expression of TKs and Leu residue replacing the common C-terminal Their Receptors in the GI Tract Met of TKs10 exert an antagonist effect through 11 NK1 receptors . In the GI tract the most abundant TK-encod- In the GI tract TKs and their receptors are lo- ing mRNAs are beta- and gamma-TAC1. TAC4 calized on many cell types, including neurons transcripts have also been detected, although and nerve fibres and exhibit a remarkable degree these are likely to be related to immune, rather of plasticity in response to environmental than motor function. A few papers have de- changes or diseases. As a matter of fact, there is scribed the expression of NKB and none that of evidence that TKs play a role in several aspects TAC3, in spite of the robust evidence (especially 70 Tachykinin receptors and gastrointestinal motility: focus on humans in animals) for the expression of NK3r in the ly emerging from the cell body) where SP could gut12. This pattern of TK gene expression im- colocalize with either somatostatin or calretinin; plies that SP and NKA are the most abundant iv) a small minority (0.5%) of type V neurons TKs in the GI tract and are always colocalized. (neurofilament-positive, small smooth cell body Thus, SP and NKA are expressed on nerve fibres with a single stem process from which very long from both extrinsic neurons and intrinsic neu- dendrites and one axon emerge). rons as well as in somata and varicosities of in- Likewise, Holzer and Holzer-Petsche13 pro- trinsic neurons. A scheme of TK expression in posed a scheme for the distribution of NK1r, the GI tract has been outlined on the basis of NK2r and NK3r based on animal studies. Accord- morphological evidence obtained in laboratory ing to this scheme, smooth muscle cells (both in animals13. According to this scheme, TKs are ex- the CM and LM) and enterocytes express both pressed in: (i) intrinsic primary afferent neurons NK1r and NK2r, whereas blood vessels and inter- (IPANs) which contain both choline acetyltrans- stitial cells of Cajal (ICC) seem to express NK1r ferase and calbindin and project to both circular only.
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