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Abstract.: The purpose of this study is to identify transient receptor potential canonical (TRPC) channels responsible for receptor-operated Ca2+ entry (ROCE) triggered by activation of endothelin type A receptor (ETAR) and to clarify the importance of calmodulin (CaM) / inositol 1,4,5-trisphosphate (IP3) receptor binding (CIRB) domain at the C terminus of TRPC channels in ETAR-activated channel regulation. In HEK293 cells coexpressing ETAR and one of seven TRPC isoforms, ETAR stimulation induced ROCE through TRPC3, TRPC5, TRPC6, and TRPC7. The TRPC3- and TRPC6-mediated ROCE was inhibited by selective inhibitors of Gq protein, phospholipase C (PLC), and CaM. The CIRB domain deletion mutants of TRPC3 and TRPC6 failed to induce ETAR-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 ETAR-operated Ca2+ channels; 2) Gq protein, PLC, and CaM are involved in TRPC3- and TRPC6-mediated ROCE; 3) ETAR-mediated activation of TRPC3 and TRPC6 requires the CIRB domain; and 4) abolition of ETAR-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.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.11162FP] Keywords:: endothelin type A receptor, receptor-operated Ca2+ influx, transient receptor potential canonical (TRPC) channel, calmodulin, CaM/IP3 receptor binding domain (CIRB)