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

1. The effect of removal of the longitudinal muscle-myenteric plexus (LM-MP) and/or indomethacin (10 microM) on the response to the tachykinin NK-2 receptor selective agonist, [beta Ala8]NKA(4-10), or to the NK-3 receptor selective agonist, senktide, was investigated by measuring mechanical activity (isotonic recording) of circular muscle (ring preparation) of the guinea-pig ileum. 2. Indomethacin (10 microM) increased the percentage of ileal rings displaying spontaneous activity, either intact or LM-MP-free. The response to senktide (10 nM and 1 microM) was lower in LM-MP-free than in intact ileal rings, either in the absence or presence of indomethacin. The response to a low concentration (10 nM) of [beta Ala8] NKA (4-10) was enhanced in LM-MP-free rings and by indomethacin. 3. In intact ileal rings, the response to senktide was unaffected by atropine (3 microM) alone or by the tachykinin NK-2 receptor antagonist MEN 10,376 (10 microM) alone while it was reduced by the combined administration of the two antagonists. The response to senktide was greatly reduced by tetrodotoxin (TTX, 1 microM). Senktide-induced contractions (10 nM) were also reduced by the blocker of N-type voltage-sensitive calcium channels, omega-contoxin (CTX, 0.1 microM). 4. In about 30% of preparations tested, an inhibitory response (decrease in spontaneous activity) to 10 nM senktide, was disclosed in CTX-treated intact ileal rings. This inhibitory effect was TTX-sensitive. 5. In LM-MP-free ileal rings, the response to senktide was abolished or reduced by atropine and MEN 10,376, alone or in combination, and was also reduced or abolished by TTX and CTX. 6. The response to [beta Ala8]NKA (4-10) was inhibited by MEN 10,376, in both intact and LM-MP-free ileal rings while it was unaffected by atropine, TTX or CTX. 7. These results indicate that indomethacin pretreatment induces a regular background activity for studying the motor response to tachykinins in the circular muscle of the ileum, probably by blocking the formation of relaxant prostanoids. A further increase in sensitivity to direct smooth muscle stimulation (NK-2 receptor agonist) can be obtained by removal of the LM-MP. The response to NK-3 receptor stimulation is diminished but not abolished by removal of the LM-MP, suggesting that NK-3 receptors are located on neuronal bodies of myenteric neurons, but possibly also at other sites (possibly, nerve terminals).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of longitudinal muscle-myenteric plexus removal and indomethacin on the response to tachykinin NK-2 and NK-3 receptor agonists in the circular muscle of the guinea-pig ileum. 751 89

Capsaicin, instilled intravesically in normal, unanesthetized rats induced a concentration-dependent bladder hyperactivity, which could be abolished by hexamethonium, given intra-arterially near the bladder, or by morphine administered intrathecally. The effect was reversible and could be repeated. The NK-2 receptor selective antagonist SR 48,968 and the nonselective NK receptor antagonist spantide, given intra-arterially near the bladder, which by themselves, in the concentrations used, did not affect cystometric parameters, both counteracted the capsaicin-induced hyperactivity, whereas the NK-1 receptor selective antagonist RP 67,580 failed to do so. Blockade of tachykinin receptors in the urinary bladder does not seem to produce changes of the micturition reflex associated with bladder filling in the conscious rat. However, tachykinins released from capsaicin-sensitive nerves by various stimuli may, through stimulation of NK-2 receptors, lower the threshold for initiation of the micturition reflex. In the rat, intravesical capsaicin may be a suitable model for studies of afferent activity caused by stimuli releasing peptides from sensory nerves in the bladder, thereby provoking bladder hyperactivity.
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PMID:Capsaicin-induced bladder hyperactivity in normal conscious rats. 751 84

The substance P receptor and the anti-substance P antibody NC1 share the ability to bind to the COOH terminus of substance P. Sequence analysis identified a direct noninterrupted homology of 5 residues in the two molecules. Replacement of Gly166 and Tyr167 in this epitope of the substance P receptor by the corresponding substance K receptor amino acids (Cys and Phe) increases the affinity toward substance P 2-fold and toward substance K and neurokinin B 11- and 21-fold, respectively. A significantly larger effect of the mutation is observed for the hexapeptides of substance P and substance K which show a mutation-induced increase in binding energy of more than 2 kcal/mol. Hence, the NH2 terminus of substance P and, to a lesser extent, of substance K masks the effect of the mutation. I conclude that the epitope is important for recognition of the common COOH terminus of the tachykinins and for preservation of selectivity. The data furthermore suggest that formation of the peptide-receptor complex occurs through a composite set of interactions which are not adequately described by the two-site/no cooperativity "address-message" model.
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PMID:Identification of an epitope in the substance P receptor important for recognition of the common carboxyl-terminal tachykinin sequence. 752 Sep 10

In this investigation the concentrations of immunoreactive substance P and neurokinin A in the hypothalamus and anterior pituitary of the Siberian hamster were compared with those in the rat and Syrian hamster. The concentrations of immunoreactive neurokinin A in the hypothalamus of Siberian hamsters were significantly higher than those of rats and Syrian hamsters, while male Siberian hamsters had similar amounts of substance P in the hypothalamus to those of male Syrian hamsters, but had higher amounts than those in male rats. However, female Siberian hamsters and significantly higher hypothalamic concentrations of both substance P and neurokinin A than did female Syrian hamsters and rats. In the anterior pituitary glands of Siberian hamsters, concentrations of substance P and neurokinin A were markedly higher than they were in rats and even more so more in Syrian hamsters. Ovariectomy further increased tachykinin concentrations in the anterior pituitary gland of female Siberian hamsters, and this was completely prevented by oestradiol replacement. Female Siberian hamsters kept under conditions of reduced photoperiod had significantly higher tachykinin concentrations in the anterior pituitary than did animals kept under daily photoperiods of 16 h light:8 h dark. The incubation of anterior pituitaries from female Siberian hamsters with a neurokinin A receptor antagonist resulted in a partial blockade of the LH and FSH release in response to LHRH. Thus, the high concentration of tachykinins present in the anterior pituitary of the Siberian hamster may have a local role in modulating the secretion or release of gonadotrophins.
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PMID:Immunoreactive substance P and neurokinin A in the hypothalamus and anterior pituitary gland of Siberian and Syrian hamsters and of rats. 752 68

Mutational analysis of the NK-1 receptor indicates that residues involved in non-peptide antagonist binding cluster around the outer portion of transmembrane segments (TM) V and VI. In contrast mutations affecting the binding of the natural peptide agonist, substance P, are scattered in the exterior part of the receptor. Recently it was reported that a number of mutations in TM-II also seriously impair substance P binding. Here we confirm that Ala substitutions for these residues located on a hydrophilic helical face of TM-II basically eliminate substance P binding to the NK-1 receptor, provided that a radiolabeled non-peptide antagonist is used as radioligand. Surprisingly, radiolabeled substance P bound well to all these mutant receptors and was displaced with only slightly reduced affinity by the unlabeled peptide and by the non-peptide antagonists. The wild-type homologous NK-2 receptor displayed properties similar to those observed in the mutated NK-1 receptors, i.e. concomitant high affinity binding of radiolabeled agonist peptide (in this case neurokinin A), yet low affinity, G-protein independent competition of unlabeled peptide with radiolabeled non-peptide antagonist. It is concluded that substitutions in TM-II of the NK-1 receptor do not affect the high affinity binding of substance P but instead block the ability of the peptides to compete for non-peptide antagonist binding. It is suggested that certain mutations can impair interchange between receptor conformations that each bind different ligands with high affinity.
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PMID:Mutations along transmembrane segment II of the NK-1 receptor affect substance P competition with non-peptide antagonists but not substance P binding. 752 69

The intracellular Ca2+ concentration ([Ca2+]i) of acinar cells of isolated submucosal glands from trachea was measured using a fluorescent dye, Fura-2. Neurokinin A (NK-A) produced a sustained rise in [Ca2+]i in a dose-dependent manner, reaching a response of 500 to 600% of the prior baseline value at 10(-6) or 10(-5) M, and the NK-A evoked [Ca2+]i was significantly higher than that by substance P (SP) at similar concentrations. NK-B did not induce significant increases in [Ca2+]i. In a Ca(2+)-free solution, NK-A produced a transient rise in [Ca2+]i, which returned to the baseline within 3 min. Mucus glycoprotein (MGP) secretion, estimated by measuring trichloroacetic-acid (TCA) precipitable glycoconjugates, was stimulated by NK-A or SP. These findings indicate that tachykinins produce a rise in [Ca2+]i by both entry from the extracellular solution and release from intracellular storage, probably by NK-2 receptor stimulation, and stimulate MGP secretion from airway submucosal glands.
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PMID:Tachykinins induce a [Ca2+]i rise in the acinar cells of feline tracheal submucosal gland. 752 23

The tachykinins substance P (SP) and neurokinin A participate in the neural control of intestinal peristalsis. This study aimed at elucidating the types of tachykinin receptors involved in SP's ability first to stimulate and then to inhibit propulsive activity. Peristalsis in the guinea pig isolated ileum was triggered by fluid-induced distension of the intestinal wall. Unlike SP, the neurokinin (NK)-1 receptor-selective agonist SP methyl ester (1-100 nM) failed to facilitate peristalsis but caused a delayed inhibition of peristaltic activity. In contrast, the NK-2 receptor-selective agonist [beta-Ala8]-NKA-(4-10) (BANKA, 1-100 nM) stimulated, but did not inhibit, peristalsis. The NK-3 receptor-selective agonist succinyl-[Asp6,N-MePhe8]-substance P-(6-11) (SENKTIDE, 0.1-10 nM) was most potent in facilitating propulsive activity, and only with 10 nM SENKTIDE was a delayed inhibition of peristalsis seen. The receptors responsible for the tachykinin-evoked stimulation and inhibition of peristaltic activity were further characterized by use of the NK-1 receptor-selective antagonist (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994, 300 nM) and the NK-2 selective antagonist (-)-N-methyl-N[4-acetylamino-4-phenyl-piperidino-2 (3,4 dichlorophenyl)butyl]-benzamide (SR-48,968, 100 nM). CP-99,994 antagonized the inhibitory effects of SP (100 nM) and SP methyl ester (100 nM) on peristalsis but did not alter the facilitation of propulsive motility brought about by SP or BANKA (100 nM). Conversely, SR-48,968 (100 nM) suppressed the ability of SP and BANKA to stimulate persitaltic activity but did not attenuate the inhibitory motor effects of SP and SP methyl ester.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Substance P stimulates and inhibits intestinal peristalsis via distinct receptors. 754 35

The aim of this study was to determine which tachykinin receptors mediate contraction in guinea pig lung parenchymal strips in vitro. Contraction caused by selective neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3) receptor agonists and the natural agonists substance P (SP) and neurokinin A (NKA) was measured in the absence or presence of the NK-1 antagonist CP-96,345 and/or the NK-2 antagonist SR 48968. The NK-1 agonist [Sar9, Met(O2)11]-substance P and the NK-2 agonist [Nle10]-neurokinin A 4-10 caused similar concentration-dependent contractions that were inhibited by CP-96,345 and SR 48968, respectively. The NK-3 agonist [MePhe7]-neurokinin B also caused contraction, albeit at 10-fold higher concentrations, and this contraction was unaffected by either the NK-1 or NK-2 antagonist or the combination of both antagonists. Either CP-96,345 or SR 48968 alone had little effect on NKA-mediated contraction but administration of both antagonists virtually eliminated force generation. SP-induced tension was partially inhibited by SR 48968 and unaffected by CP-96,345. A second NK-1 receptor antagonist CP-99,994 also had no effect on SP-mediated tension. Therefore, NK-1, NK-2, and NK-3 agonists can all cause contraction in guinea pig lung strips, NKA-induced tension is mediated by both NK-1 and NK-2 receptors, and SP-induced contraction is mediated in part by NK-2 receptors. Both the SP and the [MePhe7]-neurokinin B data suggest that activation of a third neurokinin receptor subtype that is unaffected by an NK-1 receptor antagonist or an NK-2 receptor antagonist can cause contraction in guinea pig lung strips.
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PMID:Tachykinin receptors mediating contraction of guinea pig lung strips. 754 2

1. The effects of endogenous tachykinins and related peptides on intact guinea-pig gall-bladder neurones were investigated with single-electrode voltage- and current-clamp recording techniques. 2. Pressure ejection of substance P (100 microM) caused a long lasting membrane depolarization that was associated with a decrease in input resistance. In cells that were voltage-clamped to their resting membrane potential, substance P activated an inward current. 3. The reversal potentials of the substance P-induced depolarization and inward current were congruent to 0 mV. In a low-Na+ solution, the substance P-induced depolarization and inward current were reduced in amplitude. 4. Substance P increased the excitability of neurones, as evidenced by a greater anodal break activity and an increase in the number of action potentials generated during a depolarizing current pulse. 5. Substance P, neurokinin A (NKA) and neurokinin B (NKB) were applied by superfusion to determine the relative potencies of these tachykinins. NKB was the most potent, with an EC50 of 24 nM. The EC50 values for NKA and substance P were 47.8 and 281 nM, respectively. 6. The neurokinin-3 (NK-3) receptor agonist senktide depolarized neurones with an EC50 of 6.3 nM. Neither the NK-1 receptor agonist [Sar9,Met(O2)11]-substance P nor the NK-2 receptor agonist [beta-Ala8]-NKA(4-10) caused a measurable depolarization. 7. The NK-3 antagonist [Trp7,beta-Ala8]-NKA (4-10) inhibited the responsiveness of gall-bladder neurones to substance P with a KB (dissociation constant of receptor antagonist) of 49 nM, and depressed both capsaicin-induced depolarizations and stimulus-evoked slow EPSPs. 8. These data indicate that tachykinins mediate slow EPSPs in guinea-pig gall-bladder ganglia by activating NK-3 receptors on gall-bladder neurones. It is proposed that in response to inflammation or high intraluminal pressure, tachykinins may be released within ganglia by sensory fibres and act directly on intrinsic neurones to facilitate ganglionic transmission.
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PMID:Tachykinins as mediators of slow EPSPs in guinea-pig gall-bladder ganglia: involvement of neurokinin-3 receptors. 754 33

We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.
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PMID:Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity. 756 91


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