Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies.
This article reviews the current state of knowledge about the bestrophins, a newly identified family of proteins that can function both as Cl(-) channels and as regulators of voltage-gated Ca(2+) channels. The founding member, human bestrophin-1 (hBest1), was identified as the gene responsible for a dominantly inherited, juvenile-onset form of macular degeneration called Best vitelliform macular dystrophy. Mutations in hBest1 have also been associated with a small fraction of adult-onset macular dystrophies. It is proposed that dysfunction of bestrophin results in abnormal fluid and ion transport by the retinal pigment epithelium, resulting in a weakened interface between the retinal pigment epithelium and photoreceptors. There is compelling evidence that bestrophins are Cl(-) channels, but bestrophins remain enigmatic because it is not clear that the Cl(-) channel function can explain Best disease. In addition to functioning as a Cl(-) channel, hBest1 also is able to regulate voltage-gated Ca(2+) channels. Some bestrophins are activated by increases in intracellular Ca(2+) concentration, but whether bestrophins are the molecular counterpart of Ca(2+)-activated Cl(-) channels remains in doubt. Bestrophins are also regulated by cell volume and may be a member of the volume-regulated anion channel family.
Hartzell
H Criss
HC
Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, USA. hartzell@emory.edu
Qu
Zhiqiang
Z
Yu
Kuai
K
Xiao
Qinghuan
Q
Chien
Li-Ting
LT
D000595:Amino Acid Sequence; D000818:Animals; D000075002:Bestrophins; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D013329:Structure-Activity Relationship
C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins