Neurobiology of Disease The Best Disease-Linked Cl Channel hBest1 Regulates CaV1 (L-type) Ca Channels via src-Homology-Binding Domains

Abstract

Mutations in the bestrophin-1 (Best1) gene are linked to several kinds of macular degeneration in both humans and dogs. Although bestrophins have been shown clearly to be Cl ion channels, it is controversial whether Cl channel dysfunction can explain the diseases. It has been suggested that bestrophins are multifunctional proteins: they may regulate voltage-gated Ca 2 channels in addition to functioning as Cl channels. Here, we show that human Best1 gene (hBest1) differentially modulates CaV1.3 (L-type) voltage-gated Ca 2 channels through association with the CaV subunit. In transfected human embryonic kidney 293 cells, hBest1 inhibited CaV1.3. Inhibition of CaV1.3 was not observed in the absence of the subunit. Also, the hBest1 C terminus binds to CaV subunits, suggesting that the effect of hBest1 was mediated by the CaV subunit. The region of hBest1 responsible for the effect was localized to a region (amino acids 330 –370) in the cytoplasmic C terminus that contains a predicted src-homology-binding domain that is not present in other bestrophin subtypes. Mutation of Pro 330 and Pro 334 abolished the effects of hBest1 on CaV1.3. The effect was specific to hBest1; it was not observed with mouse Best1 (mBest1), mBest2, or mBest3. Wild-type hBest1 and the disease-causing mutants R92S, G299R, and D312N inhibited CaV currents the same amount, whereas the A146K and G222E mutants were less effective. We propose that hBest1 regulates CaV channels by interacting with the CaV subunit and altering channel availability. Our findings reveal a novel function of bestrophin in regulation of CaV channels and suggest a possible mechanism for the role of hBest1 in macular degeneration.

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@inproceedings{Yu2008NeurobiologyOD, title={Neurobiology of Disease The Best Disease-Linked Cl Channel hBest1 Regulates CaV1 (L-type) Ca Channels via src-Homology-Binding Domains}, author={Kuai Yu and Qinghuan Xiao and Guiying Cui and Amy Lee and H. Criss Hartzell}, year={2008} }