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. Application of bradykinin (BK) to the spinal cord of the neonatal rat evoked depolarizations which could be recorded via either the dorsal or ventral roots. However, responses recorded via the ventral root were abolished by removal of extracellular Ca2+ or the addition of Cd2+, while responses recorded via the dorsal root were unaffected. 2. The response recorded via the ventral root was inhibited by the substance P antagonist spantide, while responses recorded via the dorsal root were unaffected. 3. Depolarizations recorded via the dorsal root were concentration-dependent with an EC50 of 30 nM. These responses were not antagonized by the BK1 selective antagonist Leu8des-Arg9BK, but were antagonized by D-Arg0Hyp3Thi5,8D-Phe7BK with a pA2 of 6.8 +/- 0.6, which is similar to the values determined for other BK2-mediated responses. 4. Application of phorbol dibutyrate (PDBu) to the spinal cord also evoked a depolarization with respect to the dorsal root. This response to PDBu was enhanced by removal of extracellular Ca2+, while the response to BK was unaffected. 5. The potent protein kinase inhibitor staurosporine reduced the response to PDBu, but did not affect the response to BK. 6. These results suggest that BK by acting on BK2 receptors can depolarize the central terminals of primary afferent nerve fibres. This response to BK does not appear to be mediated via the activation of protein kinase C. The depolarization to BK recorded via the ventral root of the spinal cord is indirect and may be secondary to the action of BK on the primary afferent terminals.
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PMID:Bradykinin-induced depolarization of primary afferent nerve terminals in the neonatal rat spinal cord in vitro. 239 Jun 85

Receptor activation and agonist-induced desensitization of the human neurokinin-2 (NK2) receptor expressed in Xenopus oocytes have been investigated. When neurokinin A (NKA) was applied repeatedly at 5-min intervals, the second and subsequent applications gave no responses. This desensitization was not observed with the specific agonists (Lys3, Gly8-R-gamma-lactam-Leu9)NKA(3-10) (GR64349) or (Nle10)-NKA(4-10). However, in the presence of the protein kinase inhibitor staurosporine, stimulation with GR64349 or (Nle10)-NKA(4-10) induced receptor desensitization. In contrast, the protein kinase C inhibitor Ro-31-8220 was not able to enhance GR64349-mediated desensitization. We created a mutation (F248S) in the third cytoplasmic loop of NK2 that impairs NKA-induced desensitization. In the presence of either staurosporine or Ro-31-8220, the mutant receptor was desensitized in response to NKA application but not to GR64349. Also, truncation mutants delta 62 and delta 87, lacking serine and threonine residues in the cytoplasmic COOH-terminal tail, were functionally active and were partially resistant to desensitization. These observations indicate that 1) there are different conformational requirements for NK2 receptor signalling and agonist-induced desensitization, 2) the third intracellular loop and the cytoplasmic tail of NK2 are functional domains important for agonist-induced desensitization, and 3) some agonists at the NK2 receptor cause much more desensitization than others and suggest that this might result from phosphorylation by receptor-specific kinases and other non-identified protein kinases.
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PMID:A single mutation of the neurokinin-2 (NK2) receptor prevents agonist-induced desensitization. Divergent conformational requirements for NK2 receptor signaling and agonist-induced desensitization in Xenopus oocytes. 749 23

The present study investigated the effect of substance P (SP) and protein kinase inhibitors (H7 and HA1004) on beta-amyloid peptide-induced proliferation of neonatal rat brain cells in primary cultures. The beta-amyloid peptide1-28 (designated as beta AP28), at nanomolar concentrations (10(-9) M), significantly (P < or = 0.05) increased the proliferation of brain cells (presumably non-neuronal) as measured by [3H]thymidine uptake into DNA (mitogenesis). The effect was dependent on time of culture, concentration of beta AP28, and presence of fetal calf serum. The supplementation of SP into cell cultures at time zero reversed the proliferative response of beta AP28. Moreover, the beta AP28-induced proliferation was inhibited by protein kinase inhibitor H7, but not by HA1004. Since H7 is a selective protein kinase C (PKC) inhibitor and SP action involves PKC, we conclude that beta AP28 induces normal brain cell proliferation through PKC pathway of cell signaling.
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PMID:Effect of substance P and protein kinase inhibitors on beta-amyloid peptide-induced proliferation of cultured brain cells. 752 54

In C6-2B rat glioma cells, agonist-stimulated cAMP accumulation is potently inhibited after the stimulation of endogenous bradykinin receptors or stably transfected substance K receptors, coupled to phosphatidylinositol hydrolysis. In the present report, pharmacological tools were used to selectively stimulate either protein kinase C or Ca2+, the two final effectors activated upon phosphatidylinositol hydrolysis, and their role in the inhibition of the C6-2B cell cAMP signaling pathway was investigated. Activation of protein kinase C by an acute treatment with phorbol 12-myristate 13-acetate or L-alpha-1-oleoyl-2-acetyl-sn-3-glycerol did not reduce, but rather enhanced, the cAMP accumulation elicited by forskolin, a direct activator of adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. This effect was antagonized by the protein kinase inhibitor H-7 and mimicked by the protein phosphatase inhibitor okadaic acid. Thapsigargin, a selective microsomal Ca(2+)-ATPase inhibitor, evoked a sustained increase in the intracellular free Ca2+ concentration, with an EC50 of 24.8 +/- 4.3 nM, and inhibited the cAMP accumulation induced by the beta-adrenergic receptor agonist isoproterenol with comparable potency (IC50 = 19.3 +/- 0.2 nM), strongly suggesting a causal relationship between the two phenomena. The inhibition by thapsigargin of isoproterenol- or forskolin-stimulated cAMP accumulation was not affected by pertussis toxin or down-regulation or inhibition of protein kinase C. Dantrolene, a blocker of Ca2+ release from intracellular stores, antagonized 1) the Ca2+ transient in response to thapsigargin and substance K and 2) the inhibitory effect of these compounds on isoproterenol- or forskolin-induced cAMP accumulation. Moreover, sequestration of intracellular Ca2+ with the cell-permeable Ca2+ chelator ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester abolished the cAMP inhibition mediated by thapsigargin. Finally, isoproterenol- or forskolin-stimulated adenylyl cyclase activity in digitonin-permeabilized cells was not affected by either thapsigargin or substance K. These data provide compelling evidence that increases in intracellular free Ca2+ concentration without activation of protein kinase C suffice and are responsible for the inhibition of cAMP accumulation in C6-2B cells.
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PMID:Ca2+ inhibition of beta-adrenergic receptor- and forskolin-stimulated cAMP accumulation in C6-2B rat glioma cells is independent of protein kinase C. 838 3

(1) The interaction of substance P (SP)-mediated synaptic transmission with general anesthetics remains unknown. (2) Intracellular recordings were obtained from guinea-pig inferior mesenteric ganglion neurons to study monosynaptic responses to exogenous SP and GABA. (3) Propofol (1-100 microM) caused an increase in SP-evoked inward current responses and a concurrent decrease in peak amplitude of the afterspike hyperpolarization of intermittently evoked action potentials. These effects were occluded by the (BK)-K+-channel-selective blocker charybdotoxin (10 nM), and prevented by the protein kinase inhibitor staurosporine (100 nM). (4) Propofol also increased GABA-evoked current (I(GABA)) responses. (5) When elicited during a SP response, I(GABA) was significantly diminished compared to control. In the presence of staurosporine (100 nM), the inhibitory effect of SP upon I(GABA) was abolished, and the propofol-induced augmentation of I(GABA) was significantly increased. (6) Thus, SP-evoked protein kinase activity produced reciprocal changes in anesthetic sensitivity of (BK)-K+- and GABA A-receptor-gated currents of these sympathetic neurons.
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PMID:Protein kinase-mediated reciprocal modulatory changes in anesthetic sensitivity of (BK)-K+- and GABA-A receptor-gated conductances in guinea-pig sympathetic neurons. 1004 88