Obligatory participation of TRP3 and/or TRPC6 in Cardiac Muscle Store Operated Calcium Entry (SOCE)

HE, XIJU; BIRNBAUMER, LUTZ; FORMOSO, KARINA; LI, SHOUTIAN; LIAO, YANHONG; SUSPERREGUY, SEBASTIAN; LIU, BENJU

Mont Ste Odile, Ottrott, France

Congreso; The 42nd Symposium on Hormones and Cell Regulation. Ion Channels in Hormonal Homeostasis: Transient Receptor Potential Channels and Calcium Signaling; 2017

Electrophysiological data indicate that store operated Ca entry channels are heterogeneous. CRAC channels are formed of Orai1 are inwardly rectifying and Ca selective, SOC channels are TRPC1-based, minimally rectifying and rather non-selective. Neither type of channels are universally functionally expressed. Cells exist (i.e. HEK-293) from which it is almost impossible to record either CRAC currents or SOC currents. Yet in all cells store depletion (eg by Thapsigargin [Tg]) generates robust Store Operated Ca2+ Entry (SOCE) when monitored with FURA2, highlighting a void our knowledge of the molecular makeup of SOCE channels. Here we report that Tg-evoked SOCE in neonatal cardiomyocytes and H9c2 cardiomyoblasts is inhibited by about 80% by 5 uM of the panTRPC inhibitor SKF96365 (SKF), a concentration that does not inhibit Orai1-based SOCE as evoked in Orai1 plus STIM1 transfected HEK293 cells. On the other hand, the Orai1 inhibitor AnCoA4, only partially inhibited Tg-evoked SOCE in neonatal cardiomyovytes and H9c2 cardiomyoblasts. This suggests participation of TRPCs in cardiomyocyte SOCE. SOCE in neonatal cardiomyocytes from Trpc3/6/7 triple knockout mice was reduced by 60% confirming the role of TRPCs in cardiac SOCE. Cardiomyocytes express TRPC1, TRPC2, TRPC3, TRPC4 and TRPC6, but not TRPC5 or TRPC7. In aggregate, the data agree with a model in which in addition to TRPC 3 an 6 (absent in the TKO), TRPC1, 2 and 4 may also contribute to the make up of cardiomyocyte SOCE channels. These TRPCs would be responsible for about 20% of SOCE. The 20% SOCE not inhibited by SKF is likely to be Orai1-based as suggested by the AnCoA4 inhibition data.