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)

Using in situ hybridization histochemistry, we examined the expression of prepro-vasoactive intestinal polypeptide (VIP) mRNAs and preprotachykinin (PPT) mRNAs which coded for substance P (SP) in the rat dorsal root ganglion (DRG) following spinal nerve transection. VIP mRNAs increased dramatically in the DRG neurons after transection of the peripheral branch of the spinal nerve (sciatic nerve), whereas PPT mRNAs showed a gradual decrease for a few weeks. Dorsal rhizotomy or axotomy of the central branch of DRG cells had little influence on VIP-mRNAs and no effect on PPT mRNA expression. These results demonstrated an activation of VIP biosynthesis in the DRG neurons due to axotomy of the peripheral branch, which was opposite to the reaction of PPT mRNA to the same treatment.
Brain Res Mol Brain Res 1989 Dec
PMID:Prepro-VIP and preprotachykinin mRNAs in the rat dorsal root ganglion cells following peripheral axotomy. 259 82

1. Loss of response after prolonged or repeated application of stimulus is generally termed desensitization. A wide variety of phenomena occurring in living organisms falls under this general definition of desensitization. There are two main types of desensitization processes: specific and non-specific. 2. Desensitization of the nicotinic acetylcholine receptor is triggered by prolonged or repeated exposure to agonists and results in inactivation of its ion channel. It is a case of specific desensitization and is an intrinsic molecular property of the receptor. 3. Desensitization of the nicotinic acetylcholine receptor at the neuromuscular junction was first reported by Katz and Thesleff in 1957. Desensitization of the receptor has been demonstrated by rapid kinetic techniques and also by the characteristic "burst kinetics" obtained from single-channel recordings of receptor activity in native as well as in reconstituted membranes. In spite of a number of studies, the detailed molecular mechanism of the nicotinic acetylcholine receptor desensitization is not known with certainty. The progress of desensitization is accompanied by an increase in affinity of the receptor for its agonist. This change in affinity is attributed to a conformational change of the receptor, as detected by spectroscopic and kinetic studies. A four-state general model is consistent with the major experimental observations. 4. Desensitization of the nicotinic acetylcholine receptor can be potentially modulated by exogenous and endogenous substances and by covalent modifications of the receptor structure. Modulators include the noncompetitive blockers, calcium, the thymic hormone peptides (thymopoietin and thymopentin), substance P, the calcitonin gene-related peptide, and receptor phosphorylation. Phosphorylation is an important posttranslational covalent modification that is correlated with the regulation and desensitization of the receptor through various protein kinases. 5. Although the physiological significance of desensitization of the nicotinic receptor is not yet fully understood, desensitization of receptors probably plays a significant role in the operation of the neuronal networks associated in memory and learning processes. Desensitization of the nicotinic receptor could also possibly be related to the neuromuscular disease, myasthenia gravis.
Cell Mol Neurobiol 1989 Jun
PMID:Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. 266 67

3H-Neurokinin A (3H-NKA) with high specific activity (75 Ci/mmol) was synthesized to study NKA (NK-2)-binding sites on membrane preparations of various tissues in the rat, including brain, spinal cord, duodenum, vas deferens, and ileum. The binding capacity of 3H-NKA (0.9 nM) was very low in membrane preparations of different central nervous system regions and the ileum smooth muscle (0.2-2 fmol/mg of protein). In contrast, relatively high specific binding was found in membrane suspensions of the rat duodenal smooth muscle (18 fmol/mg of protein) and the vas deferens (8 fmol/mg of protein). 3H-NKA-binding sites were further characterized on the rat duodenal smooth muscle. The specific binding of 3H-NKA was shown to be temperature dependent, saturable, reversible, and increased in parallel with the protein concentration. Scatchard analyses and Hill plots of equilibrium binding studies in the concentration range of 0.40-30 nM revealed that 3H-NKA bound to a single class of noninteracting binding sites (Bmax = 270 fmol/mg of protein, KD = 13.3 nM). Displacement of 3H-NKA with different tachykinin-related peptides gave the following rank order of potencies: NKA greater than NKA (4-10) greater than kassinin greater than eledoisin greater than NKB much greater than substance P greater than physalaemin, which suggests that the binding site labeled by 3H-NKA is different from substance P (NK-1)-and NKB (NK-3)-binding sites. The biological activities of tachykinins and related peptides were tested by measuring their contractile effects on the rat duodenum and rabbit pulmonary artery, two tissues known to be sensitive for NKA. Ki values were correlated with the EC50 obtained in biological assays. The results revealed a significant correlation (r = 0.86, p less than 0.01) between Ki and EC50 values obtained in the isolated rabbit pulmonary artery, whereas there was no significant correlation between binding affinities and biological responses on the rat duodenum (r = 0.62, p greater than 0.05).
Mol Pharmacol 1987 Dec
PMID:3H-neurokinin A labels a specific tachykinin-binding site in the rat duodenal smooth muscle. 282 90

The actions of mammalian tachykinins (substance P, substance K/neurokinin a, neuromedin K/neurokinin b) and non-mammalian tachykinins (eledoisin, kassinin, physalaemin) were compared on the rabbit pupillary sphincter. All acted as direct spasmogens with potencies in the order: eledoisin greater than physalaemin = neurokinin b = substance P greater than kassinin greater than neurokinin a. However, their actions could be divided into at least two categories on the basis of similar kinetics of contractions, differential sensitivity to the tachykinin antagonist (D-Arg1, D-Pro2, D-Trp7,9, Leu11) substance P and specific cross-protection against phenoxybenzamine inactivation by structurally related tachykinins. The relationship between these observations and the suggested "P" and "E" subtypes of tachykinin receptors is discussed.
Mol Pharmacol 1988 Jan
PMID:Evidence for multiple tachykinin receptor subtypes on the rabbit iris sphincter muscle. 289 26

The nicotinic acetylcholine receptor of Torpedo californica has been shown to be subject to cyclic AMP-dependent phosphorylation, raising the possibility that nicotinic receptors may be regulatable by phosphorylation. To investigate this possibility for a neuronal nicotinic receptor, we have studied the effects of elevation of cyclic AMP on the ion-conducting properties of the nicotinic receptor of PC12 cells. The cyclic AMP content of the cells was altered by exposure to various concentrations of forskolin (an activator of adenylate cyclase) for periods of time ranging from 1 to 40 min. Receptor activation then was measured as agonist-induced influx of 86Rb+ into the cells. Throughout a variety of conditions, no changes in agonist-induced ion influx were detected. This was true regardless of the concentration of agonist used, the duration of receptor stimulation that was measured, the concentration of forskolin employed, or the duration of elevation of cyclic AMP prior to receptor activation. Experiments designed to measure receptor desensitization also were unable to detect any differences upon elevation of cyclic AMP. Finally, the antagonism of receptor activation by substance P also was not affected by elevation of cyclic AMP. Thus, no evidence could be obtained in these cells supporting the hypothesis that a neuronal nicotinic acetylcholine receptor can be acutely regulated by changes in cellular cyclic AMP.
Mol Pharmacol 1984 Jul
PMID:Acute elevation of cyclic AMP does not alter the ion-conducting properties of the neuronal nicotinic acetylcholine receptor of PC12 cells. 608 18

The responses of 122 neurons in the area postrema of anesthetized dogs to 17 common transmitters and peptides were determined. Recordings were made from one barrel of a seven-barrel ionophoretic electrode. All neurons were silent at rest, but most could be detected and excited by the application of glutamate. The glutamate response was a brief, high-frequency response of less than 1-sec duration. Excitatory responses were also found to histamine, norepinephrine, serotonin, dopamine, apomorphine, angiotensin II, neurotensin, leucine enkephalin, vasoactive intestinal polypeptide, thyrotropin releasing hormone, gastrin, vasopressin, and substance P. While most neurons tested were excited by dopamine and apomorphine, approximately half of those studied were also excited by each of the other substances. Inhibitory responses were found to norepinephrine (6 of 15 cells) and histamine (3 of 45 cells). No responses were found to acetylcholine, somatostatin, or cholecystokinin. The responses to all 13 excitatory substances other than glutamate were similar. Typically these responses had a latency of 2-20 sec and lasted for 30 sec to 5 min on their first application. The frequency of discharge was usually low (approximately 0.5 Hz). Multiple applications of these agents often induced a maintained spontaneous discharge of low frequency. Each application also induced a transient incremental discharge at a frequency that rarely exceeded 2 Hz. The area postrema has been proposed to be the "chemoreceptor trigger zone" for emesis (Borison and Wang, 1953). All of the agents which excite area postrema neurons, with the exception of serotonin and norepinephrine, are emetic, while none of the three agents without excitatory effects is known to be emetic. Thus these results provide strong support for the central role of the area postrema in emesis. The similarity of response to so many substances on small neurons suggests a common ionic and/or metabolic mechanism underlying the response. The prolonged nature of the response to brief administration of these agents would seem to be appropriate for neurons which subserve a sensation and behavior such as nausea and vomiting.
Cell Mol Neurobiol 1983 Jun
PMID:Responses of neurons of canine area postrema to neurotransmitters and peptides. 614 78

Binding characteristics of 125I-labeled Bolton-Hunter substance P ([125I]BHSP), a radioactive analogue of substance P, were studied with mesencephalic primary cultures prepared from embryonic mouse brain. Nonspecific binding represented no more than 20% of the total binding observed on the cells. In contrast, significant specific binding--saturable, reversible, and temperature-dependent--was demonstrated. Scatchard analysis of concentration-dependent binding saturation indicates a single population of noninteracting sites with a high affinity (Kd = 169 pM). Substance P and different substance P analogues were tested for their competitive potencies with regard to [125I]BHSP binding. BHSP itself, substance P, (Tyr8)-substance P, and (nor-Leu11)-substance P strongly inhibited the binding. Good inhibition was also obtained with physalaemin and eledoisin, two peptides structurally related to substance P. When substance P C-terminal fragments were tested for their ability to compete with [125I]BHSP binding, a good relationship was found between competitive activity and peptide length. Regional distribution of [125I]BHSP binding sites was found using primary cultures obtained from different regions of embryonic mouse brain. Mesencephalic, hypothalamic, and striatal cultures had the highest [125I]BHSP binding capacities, whereas cortical, hippocampal, and cerebellar cells shared only little binding activity. Finally, when mesencephalic cells were grown under conditions impairing glial development, [125I]BHSP binding was not affected, demonstrating that binding sites are located on neuronal cells.
Mol Pharmacol 1982 Jul
PMID:Specific binding of an immunoreactive and biologically active 125I-labeled substance P derivative to mouse mesencephalic cells in primary culture. 618 86

The dissociation constants (Kd values) of substance P (SP), physalaemin, kassinin, and SP analogues acting on SP receptors in guinea pig ileal longitudinal muscle strips were determined by the pharmacological procedures of Furchgott [Adv. Drug Res. 3:21-55 (1966)]. This method involves analysis of the concentration-response data before and after fractional inactivation of receptors with phenoxybenzamine (2 X 10(-5) M). Estimations of the Kd values for SP were similar when phenoxybenzamine was incubated for 10, 13, or 15 min. Coincubation with high concentrations of SP protected against receptor inactivation with phenoxybenzamine, but bradykinin and serotonin did not cross-protect SP receptors. Kd values for SP were similar when trypsin was substituted for phenoxybenzamine [Kd = 8.1 +/- 4 nM (n = 9) versus 10 +/- 6 nM (n = 5)]. In atropinized preparations the Kd values obtained for physalaemin were similar to those obtained for untreated preparations [Kd = 8.0 +/- 3.6 nM (n = 5) and 12.6 +/- 3 nM (n = 4), respectively]. The effects of phenoxybenzamine on concentration-response curves for kassinin showed greater shifts to the right with phenoxybenzamine. This indicated that kassinin may interact with another population of receptors, in addition to the sites that SP and other analogues bind. A direct correlation was found between EC50 values and Kd values and Kd values for SP and SP analogues. It was estimated that, for SP, a 20% receptor occupancy is required to elicit a 50% response.
Mol Pharmacol 1983 May
PMID:The determination of dissociation constants for substance P and substance P analogues in the guinea pig ileum by pharmacological procedures. 619 Nov 90

With appropriate measures to protect 3H-substance P (3H-SP) from proteolytic degradation and from nonspecific adsorption to glass-fiber filters, we have been able to demonstrate reliably a high-affinity specific binding of 3H-SP to rat submaxillary/sublingual gland membranes with a KD of 1 nM and Bmax of 6 pmoles/g of tissue. The relative potencies of various SP fragments and related analogues in reducing 3H-SP binding parallel their potencies in stimulating phosphatidylinositol turnover, amylase release, and salivation, thus supporting an association of the observed 3H-SP binding site with the physiological SP receptors in this tissue. This binding is selectively stimulated by some divalent cations (Mn2+ greater than Mg2+ greater than Ca2+) but inhibited by several guanyl nucleotides, suggesting a possible linkage to adenylate cyclase. However, no effect of SP on either the basal or the norepinephrine-stimulated adenylate cyclase activity could be demonstrated in salivary gland homogenates.
Mol Pharmacol 1983 May
PMID:3h-substance P binding to salivary gland membranes. Regulation by guanyl nucleotides and divalent cations. 619 Nov 91

The hydrolysis of substance P is catalyzed by purified rabbit lung angiotensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1). The kcat/Km for the reaction at 37 degrees is 3.3 +/- 0.3 X 10(3) M-1 sec-1, which is 60 times less than that which has been reported for the hydrolysis of angiotensin I. The initial site of hydrolysis is the antipenultimate peptide bond, which generates the tripeptide amide (Gly-Leu-Met-NH2). This hydrolysis is inhibited by the angiotensin-converting enzyme inhibitors captopril, MK-422, and EDTA, and is dependent on the concentration of chloride ion. Both captopril and MK-422 potentiate the substance P-induced stimulation of salivation in rats. Thus, angiotensin-converting enzyme may be one of the enzymes that degrade substance P in vivo.
Mol Pharmacol 1984 Mar
PMID:Carboxyl-terminal tripeptidyl hydrolysis of substance P by purified rabbit lung angiotensin-converting enzyme and the potentiation of substance P activity in vivo by captopril and MK-422. 619 59


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