Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Jurkat and human peripheral blood T-lymphocytes, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, activated the influx of Ca(2+), Ba(2+) and Sr(2+). OAG also caused plasma-membrane depolarization in Ca(2+)-free media that was recovered by the addition of bivalent cation, indicating the activation of Na(+) influx. OAG-induced cation influx was (i) mimicked by the natural dacylglycerol 1-stearoyl-2-arachidonyl-sn-glycerol, (ii) not blocked by inhibiting protein kinase C or in the absence of phospholipase C activity and (iii) blocked by La(3+) and Gd(3+). Differently from OAG, both thapsigargin and phytohaemagglutinin activated a potent influx of Ca(2+), but little influx of Ba(2+) and Sr(2+). Moreover, the influx of Ca(2+) activated by thapsigargin and that activated by OAG were additive. Furthermore, several drugs (i.e. econazole, SKF96365, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, 2-aminoethoxy diphenylborate and calyculin-A), while inhibiting the influx of Ca(2+) induced by both thapsigargin and phytohaemagglutinin, did not affect OAG-stimulated cation influx. Transient receptor potential (TRP) 3 and TRP6 proteins have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann and Schultz (1999) Nature (London) 397, 259-263]. In both Jurkat and peripheral blood T-lymphocytes, mRNA encoding TRP proteins 1, 3, 4 and 6 was detected by reverse transcriptase PCR, and the TRP6 protein was detected by Western blotting in a purified plasma-membrane fraction. We conclude that T-cells express a diacylglycerol-activated cation channel, unrelated to the channel involved in capacitative Ca(2+) entry, and associated with the expression of TRP6 protein.
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PMID:Diacylglycerol activates the influx of extracellular cations in T-lymphocytes independently of intracellular calcium-store depletion and possibly involving endogenous TRP6 gene products. 1198 98

This article summarizes the literature on receptor-operated Ca2(+)-permeable nonselective cation channels in vascular smooth muscle cells. One of these conductances, the P2X1 receptor, is a classic ligand-gated channel, but others are likely to be mediated via G-protein-coupled receptors. The most studied receptor-operated channel in vascular myocytes is the norepinephrine-evoked nonselective cation channel in rabbit portal vein myocytes. The data regarding the transduction mechanisms and biophysical properties of whole-cell and single-channel currents in this preparation are described. The channels have a conductance of 20 to 25 pS and complex kinetic behavior with at least two open and two closed states. These channels are activated by norepinephrine and acetylcholine via G-protein-coupled receptors linked to phospholipase C and by diacylglycerol (DAG). The action of DAG occurs by a mechanism independent of protein kinase C, but other kinases may mediate the responses to norepinephrine and DAG. In addition, activation of tyrosine kinases leads to opening of this channel. Other vasoconstrictors, such as endothelin, vasopressin, serotonin, and angiotensin II, open Ca2(+)-permeable nonselective cation channels, but there may be differences between these conductances and the norepinephrine-evoked channels. A homologue of the transient receptor potential protein (TRPC6) is an essential component of the norepinephrine-activated channel in rabbit portal vein, and it is likely that this family of proteins plays an important role in mediating Ca2+ influx in vascular smooth muscle.
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PMID:Receptor-operated Ca2(+)-permeable nonselective cation channels in vascular smooth muscle: a physiologic perspective. 1203 May 34

Activation of phospholipase C (PLC)-linked receptors leads not only to Ca2+ release from the sarcoplasmic reticulum (SR) by inositol-1,4,5-trisphosphate (InsP3), but also to Ca2+ entry via opening of receptor-activated Ca2+ channels (RACCs) and store-operated Ca2+ channels (SOCs), in addition to possible contributions of Ca2+ release from non-SR stores. We review recent results on these non-SR Ca2+ fluxes. In A7r5 smooth-muscle cells (SMCs), high InSP3 concentrations release Ca2+ from a thapsigargin-insensitive store. Presumably this store corresponds to the Golgi and is filled by a Pmrl-type Ca2+ pump. Molecular candidates for RACCs and SOCs are found among the members of the TRPC channel family. Inoue and colleagues have recently demonstrated that in vascular SMCs TRPC6 is an essential part of a RACC that is activated by alpha-adrenergic stimulation via the diacylglycerol branch of phosphatidylinositol-4,5-bisphosphate hydrolysis. In TRPC4 knockout mice, contractility of SMCs appears unaffected. However, endothelium-dependent relaxation is impaired mainly due to lack of a SOC activity in endothelial cells. The best-characterized SOC current, mainly observed in blood cells, is Icrac Recently, it has been proposed that CaTI (TRPV5) forms at least part of the pore of CRAC. This view is challenged by data from our laboratory.
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PMID:Additional fluxes of activator Ca2+ accompanying Ca2+ release from the sarcoplasmic reticulum triggered by insP3-mobilizing agonists. 1216 17

The mammalian transient receptor potential canonical (TRPC) group of channels is a family of Ca2+-permeable cation channels that are activated following receptor-mediated stimulation of different isoforms of phospholipase C. In vitro TRPC proteins can form hetero- or homo-oligomeric channels. We performed single-cell RT-PCR analysis to reveal the co-expression of seven TRPC channels in identified rat aminergic neurones. All serotonergic neurones of the dorsal raphe (DR), the majority of histaminergic (tuberomamillary nucleus; TMN) and dopaminergic cells of the ventral tegmental area (VTA), as well as some GABAergic neurones from the VTA, expressed at least one variant of TRPC channels. No TRPC channel expression was found in the locus coeruleus. In raphe neurones TRPC6 and TRPC5 mRNAs occurred most frequently. In VTA and TMN co-expression of TRPC4 with TRPC5 and TRPC6 with TRPC7 was not found in individual neurones (in contrast to the whole-brain regions). Their co-expression in non-neuronal cells could not be excluded. The neonatal TRPC3 subunit was rarely seen. In DR, but not in the other nuclei studied, the expression of orexin receptors correlated with the expression of TRPC channels. We conclude that several TRPC channel populations exist in individual neurones and that their subunit co-expression pattern is region and cell-type specific.
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PMID:Co-expression of non-selective cation channels of the transient receptor potential canonical family in central aminergic neurones. 1278 73

Glomus cells in the carotid body respond to decreases in oxygen tension of the blood and transmit this sensory information in the carotid sinus nerve to the brain via neurons in the petrosal ganglion. G-protein-coupled membrane receptors linked to phospholipase C may play an important role in this response through the activation of the cation channels formed by the transient receptor potential (TRP) proteins. In the present study, expression of TRPC proteins in the rat carotid body and petrosal ganglion was examined using immunohistochemical techniques. TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7 were present in neurons throughout the ganglion. TRPC1 was expressed in only 28% of petrosal neurons, and of this population, 45% were tyrosine hydroxylase (TH)-positive, accounting for essentially all the TH-expressing neurons in the ganglion. Because TH-positive neurons project to the carotid body, this result suggests that TRPC1 is selectively associated with the chemosensory pathway. Confocal images through the carotid body showed that TRPC1/3/4/5/6 proteins localize to the carotid sinus nerve fibers, some of which were immunoreactive to an anti-neurofilament (NF) antibody cocktail. TRPC1 and TRPC3 were present in both NF-positive and NF-negative fibers, whereas TPRC4, TRPC5, and TRPC6 expression was primarily localized to NF-negative fibers. Only TRPC1 and TRPC4 were localized in the afferent nerve terminals that encircle individual glomus cells. TRPC7 was not expressed in sensory fibers. All the TRPC proteins studied were present in type I glomus cells. Although their role as receptor-activated cation channels in the chemosensory pathway is yet to be established, the presence of TRPC channels in glomus cells and sensory nerves of the carotid body suggests a role in facilitating and/or sustaining the hypoxic response.
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PMID:Distribution of transient receptor potential channels in the rat carotid chemosensory pathway. 1290 Sep 33

The TRPC family of receptor-activated cation channels (TRPC channels) can be subdivided into four subfamilies based on sequence homology as well as functional similarities. Members of the TRPC3/6/7 subfamily share common biophysical characteristics and are activated by diacylglycerol in a membrane-delimited manner. At present, it is only poorly understood whether members of the TRPC3/6/7 subfamily are functionally redundant or whether they serve distinct cellular roles. By electrophysiological and fluorescence imaging strategies we show that TRPC3 displays considerable constitutive activity, while TRPC6 is a tightly regulated channel. To identify potential molecular correlates accounting for the functional difference, we analyzed the glycosylation pattern of TRPC6 compared with TRPC3. Two NX(S/T) motifs in TRPC6 were mutated (Asn to Gln) by in vitro mutagenesis to delete one or both extracellular N-linked glycosylation sites. Immunoblotting analysis of HEK 293 cell lysates expressing TRPC6 wild type and mutants favors a model of TRPC6 that is dually glycosylated within the first (e1) and second extracellular loop (e2) as opposed to the monoglycosylated TRPC3 channel (Vannier, B., Zhu, X., Brown, D., and Birnbaumer, L. (1998) J. Biol. Chem. 273, 8675-8679). Elimination of the e2 glycosylation site, missing in the monoglycosylated TRPC3, was sufficient to convert the tightly receptor-regulated TRPC6 into a constitutively active channel, displaying functional characteristics of TRPC3. Reciprocally, engineering of an additional second glycosylated site in TRPC3 to mimic the glycosylation status in TRPC6 markedly reduced TRPC3 basal activity. We conclude that the glycosylation pattern plays a pivotal role for the tight regulation of TRPC6 through phospholipase C-activating receptors.
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PMID:N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. 1297 Mar 63

Various hormonal stimuli and growth factors activate the mammalian canonical transient receptor potential (TRPC) channel through phospholipase C (PLC) activation. However, the precise mechanism of the regulation of TRPC channel activity remains unknown. Here, we provide the first evidence that direct tyrosine phosphorylation by Src family protein-tyrosine kinases (PTKs) is a novel mechanism for modulating TRPC6 channel activity. We found that TRPC6 is tyrosine-phosphorylated in COS-7 cells when coexpressed with Fyn, a member of the Src family PTKs. We also found that Fyn interacts with TRPC6 and that the interaction is mediated by the SH2 domain of Fyn and the N-terminal region of TRPC6 in a phosphorylation-independent manner. In addition, we demonstrated the physical association of TRPC6 with Fyn in the mammalian brain. Moreover, we showed that stimulation of the epidermal growth factor receptor induced rapid tyrosine phosphorylation of TRPC6 in COS-7 cells. This epidermal growth factor-induced tyrosine phosphorylation of TRPC6 was significantly blocked by PP2, a specific inhibitor of Src family PTKs, and by a dominant negative form of Fyn, suggesting that the direct phosphorylation of TRPC6 by Src family PTKs could be caused by physiological stimulation. Furthermore, using single channel recording, we showed that Fyn modulates TRPC6 channel activity via tyrosine phosphorylation. Thus, our findings demonstrated that tyrosine phosphorylation by Src family PTKs is a novel regulatory mechanism of TRPC6 channel activity.
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PMID:Regulation of TRPC6 channel activity by tyrosine phosphorylation. 1476 72

A variety of plasmalemmal Ca2+-permeable channels, many of which are assembled from TRPC channels and are regulated by elements of the phosphatidylinositol pathway, may fulfil the role of store-operated channels (SOCs) and receptor-operated channels (ROCs). Growing evidence suggests that TRPC channels are clustered into spatially restricted microdomains that are important interaction sites for signalling molecules and for the induction of selective cellular responses. For example, TRPC1, which is activated solely by the depletion of internal stores in neurons, is assembled in a Ca2+ signalling complex, composed of the bradykinin receptor, G alpha(q) subunit, phospholipase C (PLC)beta and inositol 1,4,5-trisphosphate receptor (IP3R) whereas TRPC6, which is activated by phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis per se, is evenly distributed. Thus, differential targeting of TRPCs in microdomains allows different receptors to selectively recruit different Ca2+ entry pathways. TRPCs also co-assemble with members of the TRPP group, the polycystins. Because the polycystin proteins are thought to function as sensors of the extracellular environment, it can be hypothesized that TRPC channels are involved in a wide range of cellular functions other than those of SOCs and ROCs, including mechanotransduction.
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PMID:Assembly and gating of TRPC channels in signalling microdomains. 1510 77

The classical transient receptor potential (TRP) protein family consists of seven members which share a common gating mechanism contingent on phospholipase C activation. While some family members are thought to be activated subsequent to emptying of intracellular calcium stores, others appear to be gated by as yet undefined lipid messengers. TRPC 3, 6 and 7 form a structural and functional TRPC subfamily characterized by their sensitivity towards diacylglycerols (DAGs). TRPC6 is a non-selective cation channel that is activated by DAG in a membrane-delimited fashion, independently of protein kinase C. Depletion of internal Ca2+ stores is not required for TRPC6 activity. TRPC6 mRNA and protein are abundantly expressed in smooth muscle cells and DAG-evoked Ca2+ transients can be observed in primary myocytes derived from lung and blood vessels. Thus, TRPC6 is a promising candidate for as yet unidentified non-selective cationic channels in smooth muscle cells potentially involved in vasoconstrictor-activated cation influx and myogenic tone of resistance arteries. Recent systematic studies revealed that TRPC proteins assemble into heteromultimers predominantly within the confines of distinct TRPC subfamilies. The known principles of channel complex formation will be instrumental in assessing the physiological role of distinct TRPC proteins in living cells.
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PMID:Activation, subunit composition and physiological relevance of DAG-sensitive TRPC proteins. 1510 78

The putative ion channel subunits TRPC3, TRPC6 and TRPC7 comprise a structurally related subgroup of the family of mammalian TRPC channels. As is the case for the founding member of the TRPC family, Drosophila TRP, the ion channels formed by these proteins appear to be activated in some manner downstream of phospholipase C (PLC). Earlier studies indicating that TRPC3 could be activated by depletion of intracellular stores (i.e. that it is a store-operated channel, SOC) were subsequently shown to be attributable to constitutive activity of the channels. Studies on the mechanism of activation of TRPC6 and TRPC7 indicated that PLC-dependent activation involved diacylglycerol and was independent of G proteins or inositol 1,4,5-trisphosphate (IP3). Although TRPC3 can also be activated by diacylglycerols, there is evidence suggesting that these channels can be activated by IP3 and the IP3 receptor through a conformational coupling mechanism. We have re-examined the activation mechanism for TRPC3 in mammalian cells by using HEK293 cell lines stably expressing human TRPC3. Our data indicate that, like TRPC6 and TRPC7, TRPC3 is activated by PLC-generated diacylglycerol and is independent of G proteins or IP3. However, in an avian pre-B cell line, TRPC3 can function either as a diacylglycerol-activated channel, or as a SOC. The mechanism of regulation of TRPC3 in this cell line appears to be related to the level of expression of the protein.
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PMID:Signalling mechanisms for TRPC3 channels. 1510 79


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