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)

Protein kinase D (PKD), also called protein kinase Cmu (PKCmu), is a serine/threonine kinase that has unique enzymic and structural properties distinct from members of the PKC family of proteins. In freshly isolated rat parotid acinar salivary cells, extracellular ATP rapidly increased the activity and phosphorylation of PKD. The stimulation by ATP required high concentrations, was mimicked by the P2X(7) receptor ligand BzATP [2'- and 3'-O-(4-benzoylbenzoyl)ATP], and was blocked by Mg(2+) and 4,4'-di-isothiocyano-2,2'-stilbene disulphonate (DIDS), suggesting that activation of PKD was mediated by P2X(7) receptors, which are ligand-gated non-selective cation channels. Phorbol ester (PMA) and the activation of muscarinic and substance P receptors also increased PKD activity. PKC inhibitors blocked ligand-dependent PKD activation and phosphorylation, determined by in vitro phosphorylation studies and by phospho-specific antibodies to two activation loop sites (Ser(744) and Ser(748)) and an autophosphorylation site (Ser(916)). ATP and BzATP also increased the tyrosine phosphorylation and activity of PKCdelta, and these stimuli also increased extracellular signal-regulated protein kinase (ERK) 1/2 activity in a PKC-dependent manner. PKD activation was not promoted by pervanadate (an inhibitor of tyrosine phosphatases) and was not blocked by PP1 (an inhibitor of Src family kinases) or genistein (a tyrosine kinase inhibitor), suggesting that tyrosine kinases and phosphatases did not play a major role in PKD activation. P2X(7) receptor-mediated signalling events were not dependent on Ca(2+) entry. These studies indicate that PKC is involved in cellular signalling initiated by P2X(7) receptors as well as by G-protein-coupled receptors, and demonstrate that PKD and ERK1/2 are activated in similar PKC-dependent signalling pathways initiated by these diverse receptor types.
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PMID:P2X7 receptors activate protein kinase D and p42/p44 mitogen-activated protein kinase (MAPK) downstream of protein kinase C. 1205 8

Nocifensive behaviors induced by the intradermal injection of three different P2X receptor agonists, ATP, BzATP or alpha,beta-meATP, into a hindpaw were measured in rats that were injected intrathecally with either an NMDA (MK-801) or an NK-1 (L-703,606) receptor antagonist or were pretreated systemically with the VR1 agonist resiniferatoxin (RTX). The same procedures were performed in animals injected intradermally with either capsaicin or formalin. Spinal infusion of MK-801 (10-50 nmol/10 micro l) similarly reduced the number of nociceptive events triggered by each of the P2X agonists and was also effective against capsaicin and formalin induced behaviors. Intrathecal administration of L-703,606 (50-100 nmol/10 micro l) had its greatest antinociceptive effect against capsaicin-induced behaviors followed by ATP and BzATP. L-703,606 was completely ineffective against behaviors induced by formalin or the other P2X agonist, alpha,beta-meATP. Pretreatment with RTX 2 days prior to testing significantly decreased the number of nociceptive events caused by each of the P2X agonists as well as capsaicin and formalin (capsaicin>BzATP>ATP>formalin>alpha,beta-meATP). The remaining nociceptive events in RTX animals injected with alpha,beta-meATP were significantly higher than in animals injected with either ATP or BzATP. Intradermal administration of different P2X receptor agonists induced similar levels of nocifensive behaviors and activity at spinal NMDA receptors. Capsaicin-sensitive fibers were likely activated following injection of BzATP and ATP, but not alpha,beta-meATP, and appeared to trigger the spinal release of substance P. The differences in mechanisms employed by the different P2X agonists may be a function of respective selectivity for P2X receptor subtypes.
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PMID:Distinct neurochemical mechanisms are activated following administration of different P2X receptor agonists into the hindpaw of a rat. 1259 Nov 37