Molecular Physiology of Bestrophins: Multifunctional Membrane Proteins Linked to Best Disease and Other Retinopathies

Abstract

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 Ca2+ 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 Ca2+ channels. Some bestrophins are activated by increases in intracellular Ca2+ concentration, but whether bestrophins are the molecular counterpart of Ca2+-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.