Function and regulation of endothelin type A receptor-operated transient receptor potential canonical channels

The purpose of this study is to identify transient receptor potential canonical (trpc) channels responsible for receptor-operated ca 2+ entry (roce) triggered by activation of endothelin type a receptor (et ar) and to clarify the importance of calmodulin (cam) / inositol 1,4,5-trisphosphate (ip 3) receptor binding (cirb) domain at the c terminus of trpc channels in et ar-activated channel regulation. in hek293 cells coexpressing et ar and one of seven trpc isoforms,et ar stimulation induced roce through trpc3,trpc5,trpc6,and trpc7. the trpc3- and trpc6-mediated roce was inhibited by selective inhibitors of g q protein,phospholipase c (plc),and cam. the cirb domain deletion mutants of trpc3 and trpc6 failed to induce et ar-mediated roce. either deletion of the cirb domain or pharmacological inhibition of cam did not inhibit the targeting of these channels to the plasma membrane. these results suggest that 1) trpc3,trpc5,trpc6,and trpc7 can function as et ar-operated ca 2+ channels; 2) g q protein,plc,and cam are involved in trpc3- and trpc6-mediated roce; 3) et ar-mediated activation of trpc3 and trpc6 requires the cirb domain; and 4) abolition of et ar-induced roce by cirb domain deletion and cam inhibition is due to loss of cam binding to the channels but not loss of cell surface trpc3 and trpc6. © the japanese pharmacological society.