Control of TRPC and store-operated channels by protein kinase C.
TRPC channels are widely expressed among cells and are believed to play important roles in receptor-mediated Ca2+ signalling. We determined that the function of TRPC channels is highly regulated by protein kinase C (PKC). Application of diacylglycerol (DAG) or elevated endogenous DAG resulting from either DAG-lipase or DAG-kinase inhibition, completely prevented TRPC5 or TRPC4 activation in both HEK293 cells and DT40 cells. This inhibitory action of DAG on TRPC5 and TRPC4 channels was clearly mediated by PKC, in distinction to the stimulatory action of DAG on TRPC3 which was PKC-independent. PKC activation totally blocked TRPC3 channel-activated in response to OAG, and was restored by PKC-blockade. PKC-inhibition resulted in decreased TRPC3 channel deactivation. Store-operated Ca2+ entry in response to PLC-coupled receptor activation but not store-depletion per se, was substantially reduced by OAG or DAG-lipase inhibition in a PKC-dependent manner. The results reveal that each TRPC subtype is strongly inhibited by DAG-induced PKC activation reflecting a likely universal feedback control on TRPCs. The profound yet distinct control by PKC and DAG on the activation of TRPC channel subtypes may be the basis of a spectrum of regulatory phenotypes of expressed TRPC channels.
Venkatachalam
Kartik
K
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201, USA.
Zheng
Fei
F
Gill
Donald L
DL
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors; D004075:Diglycerides / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D011493:Protein Kinase C / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D050052:TRPC Cation Channels; D010738:Type C Phospholipases / Q000378:metabolism
D015220:Calcium Channels; D004075:Diglycerides; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D050052:TRPC Cation Channels; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium