Abstract
Bestrophin 3 (Best3), a member of bestrophin Cl channel family, is a CaCl(cGMP) channel candidate in vascular smooth muscle cells. The mechanism for its activation remains unclear. In previous studies, we reported that an autoinhibitory domain ((356)IPSFLGS(362)) existed in Best3 C-terminus and when the autoinhibitory domain was mutated, the Best3 channel was dramatically activated. In this study, we further dissected the roles of the C-terminal sequence in Best3 activation. We found that there were eight basic amino acids downstream of the AI domain within the region (384-397), which were also involved in Best3 activation. Mutations of these basic amino acids significantly activated Best3 as a Cl channel. Led by the assumption that the basic amino acids may be involved in the Best3 C-terminal membrane association through binding to membranous phospholipids, we discovered that PI3Kalpha inhibitor IV could strongly activate Best3.
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