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 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.

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

“…5) 22,23 . Intriguingly, the animal Bestrophin channel, whose narrow pathway is formed by three layers of Ile, Phe, and Phe, is an anion selective channel while the bacterial Bestrophin, which contains Ile, Ile, and Phe at the bottle neck, has been shown to be cation selective channel 22,24,25 .…”

Expression, localization, and functional properties of Bestrophin 3 channel isolated from mouse heart

“…Despite the significance of their conductance in many tissues, the molecular identity for the encoding channel remains unknown. Bestrophins have been identified as a novel family of Cl Ca (46) with multiple members expressed in different species (17). Several Bestrophin members have been shown to produce a calcium-activated chloride current (I ClCa ) when expressed heterologously (30, 33-36, 41, 46, 48, 49).…”

Generation ofBest1knockdown mice using lentiviral vector expressing small hairpin RNA

“…Bestrophin 1 (Best1) is believed to function as a chloride channel that may also serve as a regulator of intracellular calcium signaling (Hartzell et al 2008). Best1 has been shown to be permeable to chloride, thiocyanate, bicarbonate, glutamate, and gamma amino butyric acid (GABA), and Best1-mediated GABA release has recently been demonstrated to be responsible for tonic inhibition in cerebellar granule cells (Lee et al 2010).…”