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Characterization of Ca²⁺ Channels and G Proteins Involved in Arachidonic Acid Release by Endothelin-1/Endothelin_A Receptor

Departments of Neurosurgery (Y.K., K.N., N.H.) and Pharmacology (Y.K., T.M.), Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan

Endothelin-1 (ET-1) activates two types of Ca²⁺-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca²⁺ channel (SOCC) in Chinese hamster ovary cells expressing endothelin_A receptors (CHO-ET_AR). These channels can be distinguished by their sensitivity to Ca²⁺ channel blockers 1-(-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) and (R,S)-(3,4-dihydro-6,7-dimethoxy-isochinolin-1-yl)-2-phenyl-N,N-di[2-(2,3,4-trimethoxyphenyl)ethyl]acetamid mesylate (LOE 908). NSCC-1 is sensitive to LOE 908 and resistant to SK&F 96365; NSCC-2 is sensitive to both blockers, and SOCC is resistant to LOE 908 and sensitive to SK&F 96365. In this study, we examined the mechanism of ET-1–induced arachidonic acid (AA) release. Both SK&F 96365 and LOE 908 inhibited ET-1–induced AA release with the IC₅₀ values correlated to those of ET-1–induced Ca²⁺ influx. Moreover, combined treatment with these blockers abolished ET-1–induced AA release. Wortmannin and LY294002, inhibitors of phosphoinositide 3-kinase (PI3K), partially inhibited ET-1–induced AA release. LOE 908, but not SK&F 96365, inhibited ET-1–induced AA release in wortmannin-treated CHO-ET_AR. ET-1 also induced AA release in CHO cells expressing ET_AR truncated at the carboxyl terminal downstream of Cys385 (CHO-ET_AR385) or an unpalmitoylated (Cys³⁸³ Cys^385–388 Ser³⁸³Ser^385–388) ET_AR (CHO-SerET_AR), each of which is coupled with G_q or G_s/G₁₂, respectively. In CHO-SerET_AR, a dominant-negative mutant of G₁₂ inhibited AA release. SK&F 96365 inhibited ET-1–induced AA release in CHO-ET_AR385, whereas LOE 908 inhibited it in CHO-SerET_AR. These results indicate the following: 1) ET-1–induced AA release depends on Ca²⁺ influx through NSCC-1, NSCC-2, and SOCC in CHO-ET_AR; 2) G_q and G₁₂ mediate AA release through ET_AR in CHO cells; and 3) PI3K is involved in ET-1–induced AA release, which depends on NSCC-2 and SOCC.

Received March 24, 2003; accepted May 14, 2003.

Address correspondence to: Yoshifumi Kawanabe, M.D., Ph.D., Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Room 520, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail: ykawanabe{at}rics.bwh.harvard.edu

This article has been cited by other articles:

				Y. Kawanabe, N. Hashimoto, and T. Masaki Characterization of G proteins involved in activation of nonselective cation channels and arachidonic acid release by norepinephrine/{alpha}1A-adrenergic receptors Am J Physiol Cell Physiol, March 1, 2004; 286(3): C596 - C600. [Abstract] [Full Text] [PDF]