A PI3 kinase inhibitor found to activate bestrophin 3.
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.
Qu
Zhiqiang
Z
Department of Physiology, Qingdao University School of Medicine, Qingdao, Shandong, China. zqu30033@yahoo.com
Han
Xiaohua
X
Cui
Yuanyuan
Y
Li
Chunlin
C
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D005136:Eye Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors
D018118:Chloride Channels; D005136:Eye Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C491853:Vmd2L3 protein, mouse; D006152:Cyclic GMP