Abstract
Two peptides from the tachykinin family, substance P (SP) and neurokinin A (NKA), were identified as neurotransmitters (co-transmitters) of non-adrenergic non-cholinergic (NANCh) excitation in the gastrointestinal tract. The contraction of smooth muscles produced by tachykinins released from the excitatory enteric motoneurons is mediated by the NK1 and/or the NK2 tachykinin receptors. The differing contribution of these receptors in mediating the NANCh excitatory responses has been demonstrated in various regions of the intestine. The NK3 tachykinin receptors are confined only to the enteric neurons; they mediate release of different excitatory and inhibitory transmitters. The main secondary messenger pathway for all three tachykinin receptors is phosphoinositide breakdown that results in an increase of intracellular Ca2+ concentration. Signal transduction mechanisms are still not adequately known for tahykinin receptors. A multiple ionic mechanism has been proposed to mediate excitatory action of SP; it comprises activation of non-selective cationic channels, or activation of maxi Cl− channels, and/or inhibition of K+ channels. Data about the ionic mechanism underlying the NK2 receptor activation are still missing. In conclusion, SP and NKA play a physiological role as NANCh neurotransmitters in smooth muscles of the gastrointestinal tract and, therefore, tachykinins may have a significant pathophysiological relevance in humans.
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U. S. Von Euler and J. H. Gaddum, “An unidentified depressor substance in certain tissue extracts,”J. Physiol.,72, 74–87 (1931).
M. M. Chang, S. E. Leeman, and H. D. Niall, “Amino acid sequence of substance P,”Nature,232, 86–87 (1971).
J. E. Maggio, “Tachykinins,”Annu. Rev. Neurosci.,11, 13–21 (1988).
S. Nakanishi, “Mammalian tachykinin receptors,”Annu. Res. Neurosci.,14, 123–136 (1991).
H. Nawa, H. Kotani, and S. Nakanishi, “Tissue-specific generation of two preprotachykinin mRNAs from one gene by alternative RNA aplicing,”Nature,312, 729–734 (1984).
T. Bonner, H. U. Afflolter, A. C. Young, and W. S. Young, “AcDNA encoding the precursor of the rat neuropeptide neurokinin B,”Mol. Brain Res.,2, 243–249 (1987).
C. A. Maggi, R. Patacchini, P. Rovero, and A. Gichetti, “Tachykinin receptors and tachykinin receptor antagonists,”J. Auton. Pharmacol.,13, 23–93 (1993).
M. Schultzberg, T. Hokfelt, G. Nilsson, et al., “Distribution of peptide and catecholamine neurons in the gastrointestinal tract of rat and guinea-pig: immunohistochemical studies with antisera to substance P, VIP, enkephalins, somatostatin, gastrin, neurotensin and dopamine-b-hydroxylase,”Neuroscience,5, 689–744 (1980).
J. B. Furness and M. Costa,The Enteric Nervous System, Churchill Livingstone (1987).
M. Costa, J. B. Furness, and I. J. Llewellyn-Smith, “Histochemistry of the enteric nervous system,” in:Physiology of the Gastro-Intestinal Tract, L. R. Johnson (ed.), Raven Press, New York (1987), pp. 1–4.
S. J. H. Brookes, P. A. Steele, and M. Costa, “Identification and immunohistochemistry of cholinergic and non-cholinergic circular muscle motor neurons in the guinea-pig small intestine,”Neuroscience,42, 863–878 (1991).
P. Schmidt, S. S. Pouson, T. N. Rasmussen, et al., “Substance P and neurokinin A are co-distributed and co-localized in the porcine gasrointestinal tract,”Peptides,12, 964–973 (1991).
C. W. R. Shuttleworth, R. Murphy, J. B. Furness, and S. Pompolo, “Comparison of the presence and actions of substance P and neurokinin A in guinea-pigtaenia coli,”Neuropeptides,19, 23–34 (1991).
H. P. Too, J. L. Cordova, and J. E. Maggio, “A novel radioimmunoassay for neuromedin K. I. Absence of neuromedin K-like immunoreactivity in guinea-pig ileum and urinary bladder. II. Heterogeneity of tachykinins in guinea-pig tissues,”Regulat. Peptides,26, 93–105 (1989).
K. Tateishi, S. Kishimoto, H. Kobayashi, et al., “Distribution and localization of neurokinin A-like immunoreactivity and neurokinin B-like immunoreactivity in rat peripheral tissue,”Regulat. Peptides,30, 193–200 (1990).
Y. Yokota, Y. Sasai, K. Tanaka, et al., “Molecular characterization of a functional cDNA for rat substance P receptor,”J. Biol. Chem.,264, 17469–17652 (1989).
Y. Takeda, K. B. Chou, J. Takeda, et al., “Molecular cloning, structural characterization and functional expression of the human substance P receptor,”Biochem. Biophys. Res. Commun.,179, 1232–1240 (1991).
C. A. Maggi, “The mammalian tachykinin receptors,”Gen. Pharmacol.,26, 911–944 (1995).
R. M. Kris, V. South, A. Saltzman, et al., “Cloning and expression of the human substance K receptor and analysis of its role in mitogenesis,”Cell Growth Differentiation,2, 15–22 (1991).
B. J. Williams, N. R. Curtis, A. T. McKnight, et al., “Development of NK-2 selective antagonists,”Regulat. Peptides,22, 189 (1988).
C. A. Maggi, R. Patacchini, S. Giuliani, et al., “Competitive antagonists discriminate between NK-2 tachykinin receptor subtypes,”Br. J. Pharmacol.,100, 588–592 (1990)
G. Buell, M. F. Schultz, S. J. Arkinstall, et al., “Molecular characterization, expression and localization of human neurokinin 3 receptor,”FEBS Lett.,299, 90–95 (1992).
X. Edmonds-Alt, D. Bichon, J. P. Ducoux, et al., “SR 142,801, the first potent nonpeptide antagonist of the tachykinin NK3 receptor,”Life Sci. Pharmacol. Lett.,56, PL27-PL32 (1995).
P. Boden, J. M. Eden, J. Hodgson, et al., “The rational development of small molecule tachykinin NK3 receptor selective antagonist — the utilization of a dipeptide chemical library in drug design,”Bioorg. Med. Chem. Lett.,4, 1679–1684 (1994).
P. W. Manthyh, T. Gates, C. R. Manthyh, and J. E. Maggio, “Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues,”J. Neurosci.,9, 258–279 (1989).
K. Tsuchida, R. Shigemoto, Y. Yokota, and S. Nakanishi, “Tissue distribution and quantification of the mRNA for three rat tachykinin receptors,”Eur. J. Biochem.,193, 751–757 (1990).
E. F. Grady, P. Baluk, H. Wong, et al., “Localization of NK-1, NK-2 and NK-3 receptors by immunofluorescence and confocal microscopy,”in: Tachykinins' 95, Abstr., Florence, Italy (1995), p. 208.
C. A. Maggi, R. Patacchini, A. Giachetti, and A. Meli, “Tachykinin receptors in the circular muscle of the guinea-pig ileum,”Br. J. Pharmacol.,101, 996–1000 (1990).
V. P. Zagorodnyuk, P. Santicioli, and C. A. Maggi, “Different calcium influx pathways mediate tachykinin contraction in the circular muscle of guinea-pig colon,”Eur. J. Pharmacol.,255, 9–15 (1994).
A. D. Sandler, J. W. Maher, J. V. Weinstick, et al., “Tachykinins in the canine gastroesophageal junction,”Am. J. Surg.,161, 165–170 (1991).
O. Huber, C. Bertrand, N. W. Bunnett, et al., “Tachykinins mediate contraction of the human lower esophageal sphincterin vitro via acivation of NK2 receptors,”Eur. J. Pharmacol.,239, 103–109 (1993).
V. P. Zagorodnyuk and C. A. Maggi, “Neuronal tachykinin NK2 receptors mediate release of non-adrenergic non-cholinergic inhibitory transmitters in the circular muscle of guinea-pig colon,”Neuroscience,69, 644–650 (1995).
C. A. Maggi, V. P. Zagorodnyuk, and S. Giuliani, “Tachykinin NK3 receptor mediates NANC hyperpolarization and relaxation via nitrix oxide release in the circular muscle of the guinea-pig colon,”Regulat. Peptides,53, 259–274 (1994).
L. Bartho and P. Holzer, “Search for a physiological role of substance P in gastrointestinal motility,”Neuroscience,16, 1–32 (1985).
V. Bauer and H. Kuriyama, “The nature of non-cholinergic non-adrenergic transmission in longitudinal and circular muscle of the guinea-pig ileum,”J. Physiol.,330, 375–391 (1982).
J. P. Niel, R. A. R. Bywater, and G. S. Taylor, “Effect of substance P on non-cholinergic fast and slow post-stimulus depolarization in the guinea-pig ileum,”J. Auton. Nerv. Syst.,9, 573–584 (1983).
R. A. R. Bywater and G. S. Taylor, “Noncholinergic excitatory and inhibitory junction potentials in the circular smooth muscle of the guinea-pig ileum,”J. Physiol.,374, 153–164 (1986).
J. R. Crist, X. D. He, and R. K. Goyal, “The nature of non-cholinergic membrane potential responses to transmural stimulation in guinea-pig ileum,”Gastroenterology,100, 1006–1015 (1991).
V. P. Zagorodnyuk, P. Santicioli, C. A. Maggi, and A. Gichetti, “Evidence that tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitation and contraction in the circular muscle of guinea-pig duodenum,”Br. J. Pharmacol.,115, 237–246 (1995).
I. A. Vladimirova and M. F. Shuba, “Synaptic processes in smooth muscles,”Neirofiziologiya,16, 307–319 (1984).
V. P. Zagorodnyuk, P. Santicioli, and C. A. Maggi, “Tachykinin NK1 but not NK2 receptors mediate non-adrenergic non-cholinergic excitatory junction potential in the circular muscle of guinea-pig colon,”Br. J. Pharmacol.,110, 795–803 (1993).
C. A. Maggi, V. P. Zagorodnyuk, and S. Giuliani, “Specialization of tachykinin NK1 and NK2 receptors in producing fast and slow atropine-resistant neurotransmission to the circular muscle of the guinea-pig colon,”Neuroscience,63, 1137–1152 (1994).
R. A. R. Bywater and G. S. Taylor, “Non-cholinergic fast and slow post-stimulus depolarization in the guinea-pig ileum,”J. Physiol.,340, 47–56 (1983)
L. Bartho, P. Santicioli, R. Patacchini, and C. A. Maggi, “Tachykininergic transmission to the circular muscle of the guinea-pig ileum: evidence for involvement of NK-2 receptors,”Br. J. Pharmacol.,105, 805–810 (1992).
S. Guard and S. P. Watson, “Tachykinin receptor types: classification and membrane signalling mechanisms,”Neurochemistry,18, 149–165 (1991).
Y. Nakajima, K. Tsuchida, M. Negishi, et al., “Direct linkage of three tachykinin receptors to simulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected chinese hamster ovary cells,”J. Biol. Chem.,267, 2437–2442 (1992).
M. Mitsuhashi, Y. Ohashi, S. Shichijo, et al., “Multiple intracellular signaling pathways of the substance P receptor,”FASEB J., 6, A1562 (1992).
S. Sagan, A. Brunissen, H. Josien, et al., “[Pro9]SP-like and septide-like peptides trigger different pharmacological responses in CHO cells transfected with human NK-1 receptor,” in:Tachykinins' 95, Abstr., Florence, Italy (1995), p. 15.
A. W. Mangel and I. L. Taylor, “Modulation of electrical activity in gastrointestinal smooth muscle by peptides,”Regulat. Peptides,42, 1–13 (1992).
P. Holzer and I. Th. Lippe, “Substance P can contract the longitudinal muscle of the guinea-pig small intestine by releasing intracellular calcium,”Br. J. Pharmacol.,82, 259–267 (1984).
E. A. Mayer, X. P. Sun, S. Supplission, et al., “Neurokinin receptor-mediated regulation of [Ca2+]1 and Ca-sensitive ion channels in mammalian colonic muscle,”Ann. New York Acad. Sci.,632, 439–441 (1991).
G. R. Seabrook and T. M. Fong, “Thapsigargine blocks the mobilization of intracellular calcium caused by activation of human NK1 receptors expressed in Chinese hamster ovary cells,”Neurosci. Lett.,152, 9–12 (1993).
C. D. Benham and T. B. Bolton, “Comparison of the excitatory actions of substance P, carbachol, histamine and prostaglandin F2α on the smooth muscle of thetaenia of the guinea-pigcaecum,”Br. J. Pharmacol.,80, 409–420 (1982).
C. W. R. Shuttleworth, K. M. Sanders, and K. D. Keff “Inhibition of nitric oxide synthesis reveals non-cholinergic excitatory neurotransmission in the canine proximal colon,”Br. J. Pharmacol.,109, 739–747, (1993).
L. H. Clapp, M. B. Vivaudou, J. J. Singer, and J. V. Walsh, Jr., “Substance P, like acetylcholine, augments one type of Ca2+ current in isolated smooth muscle cells,”Pflügers Arch.,413, 565–567 (1989).
E. A. Mayer, D. D. Loo, W. J. Snape, Jr., and G. Sachs, “The activation of calcium and calcium-activated potassium channels in mammalian colonic smooth muscle by substance P,”J. Physiol.,420, 47–71 (1990).
K. Nakazawa, K. Inoue, K. Fujimori, and A. Tanaka, “Difference between substance P- and acetylcholine-induced currents in mammalian smooth muscle cells,”Eur. J. Pharmacol.,179, 453–456 (1990).
H. K. Lee, C. W. R. Shuttleworth, and K. M. Sanders, “Tachykinins activate non-selective cation currents in canine colonic myocytes,”Am. J. Physiol. (1996).
D. Regoli, G. Drapeau, S. Dion, and P. D'Orleans-Juste, “Pharmacological receptors for substance P and neurokinins,”Life Sci.,40, 109–117 (1987).
K. Fujisawa and Y. Ito, “The effects of substance P on smooth muscle cells and on neuro-effector transmission in the guinea-pig ileum,”Br. J. Pharmacol.,76, 279–290 (1982).
P. Holzer and U. Petsche, “On the mechanism of contraction and desensitization by substance P in the intestinal smooth muscle of the guinea-pig,”J. Physiol.,431, 549–568 (1983).
S. M. Sims, J. V. Walsh, Jr, and J. J. Singer, “Substance P and acetylcholine both suppress the same K+ current in dissociated smooth muscle cells,”Am. J. Physiol.,251, C580-C587 (1986).
E. A. Mayer, D. D. F. Loo, A. Kodner, and S. N. Reddy, “Differential modulation of [Sar9] substance P sulfone-activated K+ channels by substance P,”Am. J. Physiol.,257, G887-G897 (1989).
W. P. Sun, S. Supplission, and E. Mayer, “Chloride channels in myocytes from rabbit colon are regulated by a pertussis toxin-sensitive G-protein,”Am. J. Physiol.,264, G774-G785 (1993).
L. J. Janssen and S. M. Sims, “Substance P activates Cl− and K+ conductances in guinea-pig tracheal smooth muscle cells,”Can. J. Physiol. Pharmacol.,72, 705–710 (1994).
P. P. Bertrand and J. J. Galligan, “Contribution of chloride conductance increase to slow EPSC and tachykinin current in guinea-pig myenteric neurones,”J. Physiol.,481.1, 47–60 (1994).
K. Nakazawa, K. Inoue, K. Fujimori, and A. Tanaka, “Neurokinin A suppresses a voltage-gated K+ current in smooth muscle from ratvas deferens,”Eur. J. Pharmacol.,182, 189–192 (1990).
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Neirofiziologiya/Neurophysiology, Vol. 27, No. 5/6, pp. 425–432, September–December, 1995.
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Zagorodnyuk, V.P., Belevich, A.É., Maggi, C.A. et al. Role of tachykinins in non-adrenergic non-cholinergic excitation in smooth muscles of the gastrointestinal tract. Neurophysiology 27, 338–344 (1995). https://doi.org/10.1007/BF01081913
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DOI: https://doi.org/10.1007/BF01081913