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1 Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812–8582, Japan
2 Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606–8510, Japan
3 National Institute for Physiological Sciences, Okazaki 444–8585, Aichi, Japan
4 Department of Anatomy, the Fourth Military Medical University, Xi'an 710032, China
We investigated, by using the patch clamp technique, Ca2+-mediated regulation of heterologously expressed TRPC6 and TRPC7 proteins in HEK293 cells, two closely related homologues of the transient receptor potential (TRP) family and molecular candidates for native receptor-operated Ca2+ entry channels. With nystatin-perforated recording, the magnitude and time courses of activation and inactivation of carbachol (CCh; 100 µM)-activated TRPC6 currents (ITRPC6) were enhanced and accelerated, respectively, by extracellular Ca2+ (Ca2o+) whether it was continuously present or applied after receptor stimulation. In contrast, Ca2o+ solely inhibited TRPC7 currents (ITRPC7). Vigorous buffering of intracellular Ca2+ (Ca2i+) under conventional whole-cell clamp abolished the slow potentiating (i.e. accelerated activation) and inactivating effects of Ca2o+, disclosing fast potentiation (EC50: 
0.4 mM) and inhibition (IC50: 4 mM) of ITRPC6 and fast inhibition (IC50: 0.4 mM) of ITRPC7. This inhibition of ITRPC6 and ITRPC7 seems to be associated with voltage-dependent reductions of unitary conductance and open probability at the single channel level, whereas the potentiation of ITRPC6 showed little voltage dependence and was mimicked by Sr2+ but not Ba2+. The activation process of ITRPC6 or its acceleration by Ca2o+ probably involves phosphorylation by calmodulin (CaM)-dependent kinase II (CaMKII), as pretreatment with calmidazolium (3 µM), coexpression of Ca2+ -insesentive mutant CaM, and intracellular perfusion of the non-hydrolysable ATP analogue AMP-PNP and a CaMKII-specific inhibitory peptide all effectively prevented channel activation. However, this was not observed for TRPC7. Instead, single CCh-activated TRPC7 channel activity was concentration-dependently suppressed by nanomolar Ca2i+ via CaM and conversely enhanced by IP3. In addition, the inactivation time course of ITRPC6 was significantly retarded by pharmacological inhibition of protein kinase C (PKC). These results collectively suggest that TRPC6 and 7 channels are multiply regulated by Ca2+ from both sides of the membrane through differential Ca2+–CaM-dependent and -independent mechanisms.
(Received 2 September 2004;
accepted after revision 1 October 2004;
first published online 7 October 2004)
Corresponding author R. Inoue: Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812–8582, Japan. Email: inouery{at}pharmaco.med.kyushu-u.ac.jp
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