TRPC1 and TRPC4 Channels Contribute to Basal Cardiac Calcium Signalling via a Constitutively Active Background Calcium Entry

Abstract

Transient receptor potential (TRP) channels have been assigned to a wide array of important physiological functions but in cardiac myocytes TRPC channels are almost exclusively associated with diseases. Using TRPC1/C4 double KO or TRPC1 and TRPC4 single KO mice we investigated a putative physiological role of TRPC1/C4 channels in cardiac myocytes. We have used high-speed confocal microscopy, video-imaging and electrophysiology of single ventricular myocytes to investigate local as well as global calcium handling, contractility and electrical properties of the cells. For TRPC1/C4 dKO mice we found decreased global calcium transients, with both amplitude (20% reduction) and basal, diastolic calcium concentration (around 15%) affected. Cellular contractility was reduced by more than 35%. L-type calcium current density was constant but the calcium content of the sarcoplasmic reticulum (SR) displayed a 20% reduction. Calcium sparks showed an almost 20% reduction in amplitude while other spatiotemporal parameters were unchanged. Both Na/Ca exchanger and SR-calcium pump activity were unchanged. In Mn-quench experiments we found an almost 50% reduction of Mn entry in unstimulated conditions when comparing cells from TRPC1/C4 dKO and wt mice. Using myocytes from TRPC1 or TRPC4 single KO mice we observed a reduction of global calcium handling and SR-calcium content for both genotypes. From these data we concluded that both, TRPC1 and TRPC4 channels, play an important role for basal cardiac calcium handling.This work was supported by the DFG, BMBF and the Medical Faculty.