Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deletion analysis was used to study sites of human Neurokinin A receptor (HNKAR) necessary for signal transduction in CHO cells. Deletion of 62 and 81 amino acids from the c-terminus of HNKAR forms mutant receptors HNKAR delta 62 and HNKAR delta 81, which bind neurokinin A with high affinity but are functionally different. Wild type HNKAR and HNKAR delta 62 are functionally active whereas HNKAR delta 81 is functionally inactive. In addition, HNKAR and HNKAR delta 62 were both desensitized to the neurokinin A signal within 5 minutes. The data indicates: 1) an intact cytoplasmic tail of the HNKAR is not critical for signal transduction, but the n-terminal amino acids of the cytoplasmic tail are necessary for signaling and 2) the c-terminal 62 amino acids are not necessary for desensitization.
 ...
PMID:Regions of the human neurokinin A receptor involved in the generation of second messengers and in receptor desensitization. 813 3

It is known that tachykinins (substance P, neurokinin A) participate in the excitatory neural pathways subserving peristaltic motor activity in the intestine. The aim of the present study was to elucidate the types of tachykinin receptor (NK-1 or NK-2) involved in peristalsis by the use of receptor subtype-selective antagonists. Peristaltic motility in isolated segments of the guinea-pig ileum was induced by pumping fluid into the oral end of the intestinal segment. By way of the intraluminal pressure the compliance of the intestinal wall during the preparatory phase and the pressure threshold to trigger the emptying phase of peristalsis were recorded. The tachykinin antagonists were used at concentrations that were at least 30 times in excess of the equilibrium dissociation constants which had previously been evaluated with receptor subtype-selective agonists on the guinea-pig ileum circular muscle. The NK-1 selective antagonist CP-96,345 (0.3 microM) had a slight stimulant influence on peristalsis, whereas the NK-2 selective antagonists MEN-10,376 (10 microM), GR-94,800 (0.3 microM) and SR-48,968 (0.1 microM) led to a small inhibition of motor activity. However, when given after exposure of the ileum to a threshold concentration of atropine (5-20 nM) causing little depression of peristalsis, the tachykinin NK-2 receptor antagonists invariably abolished peristalsis. This synergistic interaction was not seen when SR-48,968 was administered after the ileal segments had been exposed to concentrations of hexamethonium, isoproterenol or calcitonin gene-related peptide that by themselves caused a slight inhibition of peristalsis only.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Synergistic role of muscarinic acetylcholine and tachykinin NK-2 receptors in intestinal peristalsis. 817 May 3

Tachykinin receptors mediating uterotonic effects were examined in preparations from oestrogen-primed rats. In the absence of peptidase inhibitors [Lys5-MeLeu9-Nle10] NKA (4-10) was 14-fold more potent than neurokinin A (NKA), but the two peptides were equipotent in the presence of phosphoramidon alone and in combination with amastatin. The NK-2 receptor antagonist SR 48968 antagonised responses to the tachykinins. These findings indicate that an NK-2 receptor is present in the oestrogen-primed rat uterus and that endopeptidase 24.11 plays a major role to inactivate NKA in this tissue.
 ...
PMID:Tachykinin receptors in the rat isolated uterus. 821 May 2

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively). The antagonism exerted by MEN 10,573 and MEN 10,612 was of competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists. 823 1

The site of action of resiniferatoxin (RTX) and capsaicin and the pharmacological consequences of the resultant tachykinin release were examined in the guinea pig trachea. RTX and capsaicin were both potent and efficacious contractors of isolated tracheal smooth muscle. RTX was about 20-fold more potent than capsaicin, with -log (M) EC50 values of 8.88 +/- 0.09 (n = 14) and 7.55 +/- 0.07 (n = 14), respectively. The putative capsaicin receptor antagonist capsazepine (10 microM) effectively inhibited responses to both RTX and capsaicin in a competitive fashion. The -log (M) pKB values for capsazepine against resiniferatoxin and capsaicin were 6.28 +/- 0.25 and 6.04 +/- 0.13, respectively. Contractile responses to RTX and capsaicin were unaffected by the NK-1 antagonist CP 96345 (0.3 microM), partially inhibited by the NK-2 antagonist SR 48968 (0.3 microM) but nearly abolished by a combination of the antagonists. Capsaicin and RTX desensitized tissues to subsequent additions of either capsaicin (1 microM) or RTX (0.1 microM). Capsaicin showed maximal desensitization at 1 microM, and RTX at 0.1 microM. This study shows that RTX is a potent activator of capsaicin-sensitive tachykinin-containing nerves in the airways. The site of action of RTX and capsaicin appears to be a receptor sensitive to capsazepine. Moreover, RTX and capsaicin both release tachykinins that act on both NK-1 and NK-2 receptor subtypes.
 ...
PMID:Inhibition by capsazepine of resiniferatoxin- and capsaicin-induced contractions of guinea pig trachea. 830 98

Functional cDNA clones for hamster neurokinin-2 receptor (NK-2R) were isolated from hamster urinary bladder using a polymerase chain reaction-based methodology. The hamster NK-2R consists of 384 amino acids with a relative molecular weight of 43,418. Hamster NK-2R shares significant amino acid sequence homology with other tachykinin receptors, particularly with rat, bovine, and human NK-2R (94.3, 84.4, and 86.5%, respectively). To examine the pharmacology of cloned hamster NK-2R, we transfected mouse erythroleukemia cells with this receptor, prepared high speed membranes, and studied the receptor properties utilizing the ligand [4,5-3H-Leu9]NKA in a receptor-binding assay. For pharmacological comparison, we also transfected the human NK-2R into mouse erythroleukemia cells. [3H]NKA bound to hamster NK-2R receptor in a protein-dependent, high affinity (Kd1 = 4.14 +/- 0.31 nM), saturable (Bmax1 = 679 +/- 26 fmol/mg of protein), and highly specific manner (89 +/- 2%). A smaller population (10% density) of lower affinity receptors (Kd2 = 150 +/- 92 nM), was also observed in competition experiments. [3H]NKA bound to the human receptor with significantly higher affinity and overall greater receptor density (Kd1 = 0.37 +/- 0.11 nM, Bmax1 = 234 +/- 175 fmol/mg of protein; Kd2 = 9.0 +/- 2 nM, Bmax2 = 1989 + 990 fmol/mg of protein). [3H]NKA binding to both hamster and human receptors was enhanced greatly by divalent cations, whereas GTP analogs weakly inhibited binding to hamster receptor, but potently inhibited binding to the human receptor. Competition experiments with agonists demonstrated binding to high and low affinity states of NK-2 receptors, with identical order of potency in hamster or human NK-2R; NKA > [Nle10]NKA(4-10) > [beta-Ala8]NKA(4-10) >> substance P >>> Senktide. However, remarkable differences were observed in studies with selective NK-2 antagonists (hamster, SR48,968 > L659,877 > R396 >> MEN10,376 versus human, SR48,968 > MEN10,376 > L659,877 > R396). The rank order of antagonist affinity is consistent with the observations of NK-2 receptor pharmacology in the native tissues.
 ...
PMID:Isolation and pharmacological characterization of a hamster urinary bladder neurokinin A receptor cDNA. 830 85

We have cloned a cDNA encoding the human ileal neurokinin-2 (NK-2) receptor which mediates powerful neurokinin A-stimulated arachidonic acid (AA) and prostaglandin release when expressed in CHO cells. Two major signal transduction events appear to underlie this response. Firstly, AA liberation is critically dependent upon agonist-stimulated influx of extracellular Ca2+ although not release from intracellular stores. Secondly, NK-2 receptor-linked AA mobilization requires concomitant PKC activation and based upon limited subtype immunodetectability as well as toxin, identical pretreatment inhibits AA release partially and blocks PKC alpha translocation completely. These observations indicate that in this cell system AA liberation reflects NK-2 receptor-dependent activation of two distinct but converging signal transduction pathways regulated by different G-protein species and involving Ca2+ influx and PKC alpha activation.
 ...
PMID:Calcium influx and protein kinase C alpha activation mediate arachidonic acid mobilization by the human NK-2 receptor expressed in Chinese hamster ovary cells. 830 61

This study investigates the role of peripheral tachykinin receptors in the initiation of reflex urinary bladder contractions in urethane-anesthetized rats. Intravenous administration of the selective tachykinin neurokinin (NK)-1 receptor agonist [Sar9]substance P (SP) sulfone (0.3-30 nmol/kg) or of the selective tachykinin NK-2 receptor agonist [beta Ala8]NK-A(4-10) (0.3-100 nmol/kg) produced dose-related bladder contractions. Among NK-3 receptor agonists, senktide (1-100 nmol/kg) was not effective; [MePhe7] NK-B (3-100 nmol/kg) induced bladder contraction, but the magnitude of the response was only 20 to 25% of that produced by NK-1 or NK-2 agonists. The NK-1 receptor antagonist GR 82,334 (0.1 mumol/kg i.v.) blocked the urinary bladder contraction induced by [Sar9]SP sulfone (1 nmol/kg i.v.), but not that induced by [beta Ala8]NK-A(4-10). On the contrary, the NK-2 receptor antagonist L 659,877 (0.1-1 mumol/kg i.v.) abolished the effect of [beta Ala8] NK-A(4-10) (1 nmol/kg i.v.), but failed to affect the response to [Sar9]SP sulfone. The combined administration of GR 82,334 (0.1 mumol/kg i.v.) and L 659,877 (1 mumol/kg i.v.) blocked the tonic bladder contraction induced by topical application of capsaicin in pelvic ganglionectomized rats (efferent response of sensory nerves), but did not affect the hexamethonium-sensitive phasic reflex bladder contractions evoked by capsaicin in sham-operated rats (chemonociceptive micturition reflex). GR 82,334 (0.1 mumol/kg i.v.) or L 659,877 (1 mumol/kg i.v.), alone or in combination, did not modify cystometric parameters of the volume-evoked micturition reflex.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Evidence against a peripheral role of tachykinins in the initiation of micturition reflex in rats. 838 46

The intrastriatal injection of [Nle10]-NKA(4-10), a neurokinin A agonist, (0.05-5 ng/mouse) elicited vigorous contralateral rotations. This behavior was dose-dependently antagonized by SR 48968 (ED50: 0.15 mg/kg i.p.: 0.19 mg/kg p.o.), a selective non-peptide antagonist of NK-2 receptors, but it was not affected by spiroperidol. This suggests that NK-2 receptor stimulation may affect the activity of the striatum without necessarily involving dopaminergic systems.
 ...
PMID:Turning behavior induced in mice by a neurokinin A receptor agonist: stereoselective blockade by SR 48968, a non-peptide receptor antagonist. 838 52

Distension of a balloon placed in the proximal colon of anesthetized, guanethidine- and naloxone-pretreated guinea pigs elicited a series of long-lasting regular phasic pressure waves which were suppressed by hexamethonium. Activity evoked by a low degree of balloon distension was largely, but not completely, suppressed by atropine. Further balloon distension in atropine-treated animals enabled us to study the effect of tachykinin receptor antagonists on the atropine-resistant and hexamethonium-sensitive response to distension. The selective tachykinin receptor antagonists, (+/-)-CP 96,345 for the NK-1 receptor and L 659,877, MEN 10,376 and SR 48,968 for the NK-2 receptor, inhibited with varying potency the atropine-resistant response to distension. These antagonists also blocked the contraction of the guinea pig colon produced by the i.v. administration of selective NK-1 and NK-2 receptor agonists. In vitro experiments, using mucosa-free circular muscle strips from the guinea pig colon, proved the existence of functional NK-1 and NK-2 receptors in this tissue. We conclude that both NK-1 and NK-2 receptors participate in the atropine-resistant reflex contractions produced by localized balloon distension of the guinea pig colon in vivo.
 ...
PMID:Tachykinins and reflexly evoked atropine-resistant motility in the guinea pig colon in vivo. 838 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>