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The Journal of Neuroscience, May 28, 2008, 28(22):5660-5670; doi:10.1523/JNEUROSCI.0065-08.2008

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Neurobiology of Disease
The Best Disease-Linked Cl^– Channel hBest1 Regulates Ca_V1 (L-type) Ca²⁺ Channels via src-Homology-Binding Domains

Kuai Yu,¹ Qinghuan Xiao,¹ Guiying Cui,² Amy Lee,^2,3 and H. Criss Hartzell^1,3

Departments of ¹Cell Biology and ²Pharmacology, and ³Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322

Correspondence should be addressed to H. Criss Hartzell, Department of Cell Biology, Emory University School of Medicine, 535 Whitehead Building, 615 Michael Street, Atlanta, GA 30322. Email: criss.hartzell{at}emory.edu

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 Ca²⁺ channels in addition to functioning as Cl^– channels. Here, we show that human Best1 gene (hBest1) differentially modulates Ca_V1.3 (L-type) voltage-gated Ca²⁺ channels through association with the Ca_Vβ subunit. In transfected human embryonic kidney 293 cells, hBest1 inhibited Ca_V1.3. Inhibition of Ca_V1.3 was not observed in the absence of the β subunit. Also, the hBest1 C terminus binds to Ca_Vβ subunits, suggesting that the effect of hBest1 was mediated by the Ca_Vβ 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 Pro³³⁰ and Pro³³⁴ abolished the effects of hBest1 on Ca_V1.3. 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 Ca_V currents the same amount, whereas the A146K and G222E mutants were less effective. We propose that hBest1 regulates Ca_V channels by interacting with the Ca_Vβ subunit and altering channel availability. Our findings reveal a novel function of bestrophin in regulation of Ca_V channels and suggest a possible mechanism for the role of hBest1 in macular degeneration.

Key words: macular degeneration; retinal pigment epithelium; ion channel; calcium; src-homology; chloride

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Received Sept. 11, 2007; revised March 20, 2008; accepted April 20, 2008.

Correspondence should be addressed to H. Criss Hartzell, Department of Cell Biology, Emory University School of Medicine, 535 Whitehead Building, 615 Michael Street, Atlanta, GA 30322. Email: criss.hartzell{at}emory.edu

This article has been cited by other articles:

				Z. Qu, W. Cheng, Y. Cui, Y. Cui, and J. Zheng Human Disease-causing Mutations Disrupt an N-C-terminal Interaction and Channel Function of Bestrophin 1 J. Biol. Chem., June 12, 2009; 284(24): 16473 - 16481. [Abstract] [Full Text] [PDF]

				Y. Zhang, B. R. Davidson, W. D. Stamer, J. K. Barton, L. Y. Marmorstein, and A. D. Marmorstein Enhanced Inflow and Outflow Rates Despite Lower IOP in Bestrophin-2-Deficient Mice Invest. Ophthalmol. Vis. Sci., February 1, 2009; 50(2): 765 - 770. [Abstract] [Full Text] [PDF]

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