Obligatory Participation of TRPC3 and/or TRPC6 in Cardiac Muscle Store Operated Ca2+ Entry (SOCE). Pharmacologic and Genetic Evidence

FORMOSO, KARINA; SUSPERREGUY SEBASTIAN; XIJU HE2; SHOUTIAN LI; BENJU LIU; LUTZ BIRNBAUMER; YANHONG LIAO

Mont Ste Odile, Ottrott, France

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

European Society of Endocrinology

Electrophysiological data indicate thatstore operated Ca entry channels are heterogeneous. CRAC channels are formed ofOrai1 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 isalmost impossible to record either CRAC currents or SOC currents. Yet in allcells store depletion (eg by Thapsigargin [Tg]) generates robust Store OperatedCa2+ Entry (SOCE) when monitored with FURA2, highlighting a void our knowledgeof the molecular makeup of SOCE channels. Here we report that  Tg-evokedSOCE in neonatal cardiomyocytes and H9c2 cardiomyoblasts is inhibited byabout  80% by 5 uM of the panTRPCinhibitor SKF96365 (SKF), a concentration that does not inhibit Orai1-basedSOCE as evoked in Orai1 plus STIM1 transfected HEK293 cells. On the other hand,the Orai1 inhibitor AnCoA4, only partially inhibited Tg-evoked SOCE in neonatalcardiomyovytes and H9c2 cardiomyoblasts. This suggests participation of TRPCs in cardiomyocyte SOCE. SOCE inneonatal cardiomyocytes from Trpc3/6/7 triple knockout  mice was reduced by 60% confirming the roleof TRPCs in cardiac SOCE. Cardiomyocytes express TRPC1, TRPC2, TRPC3, TRPC4 andTRPC6, but not TRPC5 or TRPC7. In aggregate, the data agree with a model inwhich  in addition to TRPC 3 an 6 (absentin the TKO), TRPC1, 2 and 4  may alsocontribute to the make up of cardiomyocyte SOCE channels. These TRPCswould  be responsible for about 20% ofSOCE. The 20% SOCE not inhibited by SKF is likely to be Orai1-based assuggested by the  AnCoA4 inhibition data.