Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vomeronasal sensory neurons play a crucial role in detecting pheromones, but the chemoelectrical transduction mechanism remains unclear and controversial. A major barrier to the resolution of this question has been the lack of an activation mechanism of a key transduction component, the TRPC2 channel. We have identified a Ca(2+)-permeable cation channel in vomeronasal neuron dendrites that is gated by the lipid messenger diacylglycerol (DAG), independently of Ca(2+) or protein kinase C. We demonstrate that ablation of the TRPC2 gene causes a severe deficit in the DAG-gated channel, indicating that TRPC2 encodes a principal subunit of this channel and that the primary electrical response to pheromones depends on DAG but not Ins(1,4,5)P(3), Ca(2+) stores, or arachidonic acid. Thus, a previously unanticipated mechanism involving direct channel opening by DAG underlies the transduction of sensory cues in the accessory olfactory system.
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PMID:A diacylglycerol-gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: mechanism of pheromone transduction. 1464 79

In the heart, fibroblasts play an essential role in the deposition of the extracellular matrix and they also secrete a number of hormonal factors. Although natriuretic peptides, including C-type natriuretic peptide (CNP) and brain natriuretic peptide, have antifibrotic effects on cardiac fibroblasts, the effects of CNP on fibroblast electrophysiology have not been examined. In this study, acutely isolated ventricular fibroblasts from the adult rat were used to measure the effects of CNP (2 x 10(-8) M) under whole-cell voltage-clamp conditions. CNP, as well as the natriuretic peptide C receptor (NPR-C) agonist cANF (2 x 10(-8) M), significantly increased an outwardly rectifying non-selective cation current (NSCC). This current has a reversal potential near 0 mV. Activation of this NSCC by cANF was abolished by pre-treating fibroblasts with pertussis toxin, indicating the involvement of G(i) proteins. The cANF-activated NSCC was inhibited by the compounds Gd(3+), SKF 96365 and 2-aminoethoxydiphenyl borate. Quantitative RT-PCR analysis of mRNA from rat ventricular fibroblasts revealed the expression of several transient receptor potential (TRP) channel transcripts. Additional electrophysiological analysis showed that U73122, a phospholipase C antagonist, inhibited the cANF-activated NSCC. Furthermore, the effects of CNP and cANF were mimicked by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG), independently of protein kinase C activity. These are defining characteristics of specific TRPC channels. More detailed molecular analysis confirmed the expression of full-length TRPC2, TRPC3 and TRPC5 transcripts. These data indicate that CNP, acting via the NPR-C receptor, activates a NSCC that is at least partially carried by TRPC channels in cardiac fibroblasts.
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PMID:C-type natriuretic peptide activates a non-selective cation current in acutely isolated rat cardiac fibroblasts via natriuretic peptide C receptor-mediated signalling. 1720 1

Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A(2) inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review summarizes the data on pharmacological modification of TRPC3/6/7. Sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, skeletive and more potent modulators of TRPC3/6/7 activity.
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PMID:Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. 2093 61

Canonical transient receptor potential (TRPC) Ca(2+)-permeable channels are members of the mammalian TRP super-family of cation channels, and have the closest homology to the founding members, TRP and TRPL, discovered in Drosophila photoreceptors. The TRPC subfamily is composed of 7 subunits (C1-C7, with TRPC2 a pseudogene in humans), which can all combine with one another to form homomeric and heteromeric structures. This review focuses on mechanisms involved in opening TRPC channels (i.e. gating mechanisms). It initially describes work on the involvement of phosphatidylinositol-4,5-bisphosphate (PIP(2)) and diacylglycerol (DAG) in gating TRP and TRPL channels in Drosophila, and then discusses evidence that similar gating mechanisms are involved in opening mammalian TRPC channels. It concludes that there are two common activation pathways of mammalian TRPC channels. Non-TRPC1-containing channels are opened by interactions between DAG, the direct activating ligand, and PIP(2), which acts as a physiological antagonist at TRPC proteins. Competitive interactions between an excitatory effect of DAG and an inhibitory action of PIP(2) can also be modulated by IP(3) acting via an IP(3) receptor-independent mechanism. In contrast TRPC1-containing channels are gating by PIP(2), which requires PKC-dependent phosphorylation of TRPC1 proteins.
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PMID:Gating mechanisms of canonical transient receptor potential channel proteins: role of phosphoinositols and diacylglycerol. 2129 Mar 8