Localization of the neurokinin 1 (NK-1) receptor in the human antrum and duodenum

doi:10.1016/S0304-3940(98)00618-1

Neuroscience Letters

Volume 253, Issue 1, 28 August 1998, Pages 49-52

https://doi.org/10.1016/S0304-3940(98)00618-1 Get rights and content

Abstract

A newly available antibody to the neurokinin-1 receptor (NK-1r) has made it possible to determine the distribution of the NK-1r receptor in human tissue. In the present study the distribution of the NK-1r and substance P have been determined in the human antrum and duodenum by immunocytochemistry. The NK-1r was present on myenteric and submucosal neurons and nerve fibers of the gastro-enteric nervous system. In addition, the receptor was present on spindle-shaped cells in the circular muscle layer, endothelial cells and a population of mucosal cells. In the submucosal plexus NK-1r immunoreactive neurons were surrounded by substance P containing fibers. These results indicate an extensive cellular expression of the NK-1r in the human antrum and duodenum.

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Cited by (21)

Regional differences of tachykinin effects on smooth muscle and pacemaker potentials of the stomach, duodenum, ileum and colon of an emetic model, the house musk shrews
2023, Neuropeptides
Citation Excerpt :
NK2, but not NK1, is also predominantly involved in the contraction of the human lower esophageal sphincter (Huber et al., 1993). No functional studies were performed on the human stomach, while NK1 and NK2 were found expressed in the human stomach (Candenas et al., 2002; Smith et al., 1998). The study on the mechanism of actions for NK1-selective antagonists as anti-emetics focus on the area postrema at the brainstem (Ibrahim and Preuss, 2022), while the involvement of tachykinins on GI-related therapeutics or side effects remain largely unknown (Lecci et al., 2008; Sanger, 2004).
The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus.
The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK₁ (CP122,721, CP99,994), NK₂ (SR48,968, GR159,897) and NK₃ (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array.
Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK₃ had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon.
This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.
Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human
2006, Autonomic Neuroscience: Basic and Clinical
Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be sufficient to disrupt physiological motor and, possibly, secretory activity at the colonic level. Available evidence indicates that, in healthy volunteers, the infusion of NKA (25 pmol/kg/min i.v.) stimulated small intestine motility and precipitated a series of intestinal and non-intestinal adverse events. Nepadutant (8 mg i.v.), a selective NK2 receptor antagonist, antagonised small intestine motility induced by NKA and prevented associated intestinal adverse events. In another study, the same dose of nepadutant increased colo-rectal compliance during isobaric balloon distension in healthy volunteers pretreated with a glycerol enema, disclosing a NK2 receptor-mediated component in the regulation of colonic smooth muscle tone. However, the prolonged blockade of NK2 receptors by nepadutant (16 mg i.v. b.i.d. for 8 days) did not affect bowel habits, neither in term of movements nor of stool consistency. Altogether, these results indicate that, even when there is a significant redundance in the effects of TKs and in the role of their receptors, the selective blockade of tachykinin NK2 receptors can have functional consequences on human intestinal motility and perception, but this can occur without the disruption of the physiological functions.
Expression of the neurokinin type 1 receptor in the human colon
2006, Autonomic Neuroscience: Basic and Clinical
The distribution of the neurokinin type 1 receptor (NK1r) in human intestine, mapped in a few immunohistochemical investigations in the antrum and the duodenum, is comparable to that widely studied in rodents. Importantly, despite pharmacological evidence of their presence in mammalian intestinal muscle, their immunohistochemical visualization in smooth muscle cells remains to be determined in human digestive tract. In the present work, we studied the distribution of NK1r in the human colon, with a particular view to visualize their expression in muscle cells. With this aim, part of colonic segments were incubated with nicardipine and TTX in order to induce accumulation of the NK1r on cell membrane. NK1r were visualized by using immunohistochemistry combined with fluorescence and confocal microscopy. Without incubation, NK1r-IR was clearly observed on the membrane and the cytoplasm of myenteric and submucous neurons and interstitial cells of Cajal, but could not be clearly determined in the longitudinal and circular muscle. NK1r-IR-expressing neurons and interstitial cells were closely surrounded by substance P (SP) immunoreactive nerves. Incubation of colonic segments with nicardipine and TTX at 4 °C for 1 h with SP allowed to reveal a strong NK1r-IR at the surface of muscle cells. Incubation with SP (10^− 6 M) at 37 °C for 1 min induced a relocation of NK1r-IR into the cytoplasm of muscle. This is interpreted as an internalization of NK1r induced by the binding of SP on muscular NK1r. The present data contribute to emphasize the role of NK1r in tachykinin-mediated neuronal processes regulating intestinal motility.
Cellular expression of the neurokinin 1 receptor in the human antrum
2000, Journal of the Autonomic Nervous System
The localization of the neurokinin 1 receptor in rat and guinea pig gastrointestinal tract has been extensively studied but not in human tissues. The present study used antibodies to characterize the cellular expression of neurokinin 1 receptors in human antrum. Cryostat sections (40–80 μm) were immunostained for the neurokinin 1 receptor double labeled with substance P, von Willebrand’s factor, c-kit, fibronectin, S-100, serotonin, gastrin and somatostatin. Neurokinin 1 receptor-immunoreactivity was observed on neurons within the myenteric and submucosal plexuses surrounded by substance P-immunoreactive fibers and on von Willebrand’s factor-immunoreactive endothelial cells lining blood vessels throughout the antral wall. c-Kit-immunoreactive interstitial cells of Cajal and gastrin cells were co-stained by the monoclonal neurokinin 1 receptor antibody. Finally, there was no evidence for the presence of the neurokinin 1 receptor on fibroblasts, Schwann, somatostatin, serotonin or smooth muscle cells. This study clearly demonstrates an expanded cellular expression of the neurokinin 1 receptor in the human antrum.
A monoclonal antibody directed against the neurokinin-1 receptor contains a peptide sequence with similar hydropathy and functional properties to substance P, the natural ligand for the receptor
2000, Molecular Immunology
Monoclonal antibody (mAb) PS12, obtained using the complementary peptide methodology, mimics the neuropeptide substance P (SP) in recognizing the SP-binding domain of the neurokinin-1 receptor (NK1R) and eliciting production of polyclonal antibodies cross-reacting with SP with a high affinity (Déry et al., 1997. J. Neuroimmunol. 76, 1–9). The aim of the present study was to investigate which structural features of mAb PS12 might account for this molecular mimicry. Cloning and sequencing of variable regions of both light (VL) and heavy (VH) chains of this ‘SP-like’ antibody did not indicate any primary sequence homology between SP and any antibody region. Instead, they revealed a striking similarity between the hydropathic profile of SP and that of an 11-amino-acid region in the light chain encompassing the second complementarity determining region (CDR2). When applied to CHO cells expressing the human NK1R, a synthetic extended 17-amino-acid peptide (denoted CDR2L) corresponding to this VL region inhibited the high-affinity binding of radiolabeled SP and antagonized the SP-induced inositol phosphate production. Moreover, a re-examination of the sequences of several antibodies that previously served in the design of CDR-derived bioactive peptides indicated that these antibodies also carried the hydropathic image of the respective ligands that they mimic. In agreement with previous observations on artificial synthetic peptides, our data thus suggest that the molecular mimicry between natural proteins (i.e. antibody and hormone, for example) could be understood on a structural level directly related, at least in part, to hydropathic homology. These results could then guide the search for bioactive paratope-derived peptides of potential pharmacological interest. We also observed inverse hydropathy between multiple CDRs of mAb PS12 (including CDR3H and CDR3L) and the peptide epitope, confirming the importance of hydropathic complementarity in antigen–antibody interactions.
Smooth muscle cells are the site of neurokinin-1 receptor localization in the arterial supply of the rat sciatic nerve
1999, Neuroscience Letters
The occurrence and distribution of the preferred receptor for the neuropeptide, substance P (SP), the neurokinin-1 receptor (NK1R) was investigated in the vascular supply of the rat sciatic nerve. Messenger RNA for NK1R was demonstrated by RT-PCR in the epineurial layer where the majority of small arteries and arterioles feeding the endoneurial vasculature are located. Immunoreactivity to NK1R-protein was localized on the smooth muscle cells of these arterial vessels by means of immunofluorescence using a polyclonal NK1R antiserum. This muscular localization of NK1R explains the previously reported [Zochodne, D.W. and Ho, L.T., J. Physiol., 444 (1991) 615–630] moderate vasoconstrictor rather than vasodilator effects of SP in this vascular bed.

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Localization of the neurokinin 1 (NK-1) receptor in the human antrum and duodenum

Abstract

J. Neuroimmunol.

Neuroscience

Pharmacol. Ther.

J. Auton. Nerv. Syst.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas

Am. J. Physiol.

Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones

Biochemistry

Characterization of antisera specific to NK1, NK2, and NK3 neurokinin receptors and their utilization to localize receptors in the rat gastrointestinal tract

J. Neurosci.

Conformational compatibility as a basis of differential affinities of tachykinins for the neurokinin-1 receptor

Biochemistry