title: Function and regulation of endothelin type A receptor-operated transient receptor potential canonical channels.
abstract: 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(A)R) 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(A)R-activated channel regulation. In HEK293 cells coexpressing ET(A)R and one of seven TRPC isoforms, ET(A)R 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(A)R-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(A)R-operated Ca(2+) channels; 2) G(q) protein, PLC, and CaM are involved in TRPC3- and TRPC6-mediated ROCE; 3) ET(A)R-mediated activation of TRPC3 and TRPC6 requires the CIRB domain; and 4) abolition of ET(A)R-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.
authors: Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Hokkaido 060-8638, Japan.
authors: Takahiro
authors: T
authors: Horinouchi
authors: Koji
authors: K
authors: Terada
authors: Tsunaki
authors: T
authors: Higa
authors: Hiroyuki
authors: H
authors: Aoyagi
authors: Tadashi
authors: T
authors: Nishiya
authors: Hiroyuki
authors: H
authors: Suzuki
authors: Soichi
authors: S
authors: Miwa
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D044022:Receptor, Endothelin A / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D044022:Receptor, Endothelin A; D050052:TRPC Cation Channels; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium