Protection of TRPC7 cation channels from calcium inhibition by closely associated SERCA pumps.
Numerous studies have demonstrated that members of the transient receptor potential (TRP) superfamily of channels are involved in regulated Ca2+ entry. Additionally, most Ca2+-permeable channels are themselves regulated by Ca2+, often in complex ways. In the current study, we have investigated the regulation of TRPC7, a channel known to be potentially activated by both store-operated mechanisms and non-store-operated mechanisms involving diacylglycerols. Surprisingly, we found that activation of TRPC7 channels by diacylglycerol was blocked by the SERCA pump inhibitor thapsigargin. The structurally related channel, TRPC3, was similarly inhibited. This effect depended on extracellular calcium and on the driving force for Ca2+ entry. The inhibition is not due to calcium entry through store-operated channels but rather results from calcium entry through TRPC7 channels themselves. The effect of thapsigargin was prevented by inhibition of calmodulin and was mimicked by pharmacological disruption of the actin cytoskeleton. Our results suggest the presence of a novel mechanism involving negative regulation of TRPC channels by calcium entering through the channels. Under physiological conditions, this negative feedback by calcium is attenuated by the presence of closely associated SERCA pumps.
Lemonnier
Loïc
L
National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Trebak
Mohamed
M
Lievremont
Jean-Philippe
JP
Bird
Gary S
GS
Putney
James W
JW
D000255:Adenosine Triphosphate / Q000378:metabolism; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology; D002412:Cations / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D047630:Depsipeptides / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D017136:Ion Transport; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
D001896:Boron Compounds; D002147:Calmodulin; D002412:Cations; D047630:Depsipeptides; D004075:Diglycerides; D007093:Imidazoles; D007211:Indoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C498501:TRPC7 protein, human; C057531:jasplakinolide; D003571:Cytochalasin B; C031938:calmidazolium; D019284:Thapsigargin; C038237:1-oleoyl-2-acetylglycerol; D000255:Adenosine Triphosphate; D005682:Gadolinium; C109986:2-aminoethoxydiphenyl borate; D000252:Calcium-Transporting ATPases; D002118:Calcium; C000543:cyclopiazonic acid