{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Bestrophin‐1 (BEST1) is an integral membrane protein primarily expressed in the retinal pigment epithelium (RPE) that functions as a calcium‐activated chloride channel. A wealth of studies demonstrates that BEST1 mediates Cl⁻ efflux in response to rises in intracellular Ca²⁺ and, in some systems, also conducts HCO₃⁻, thereby contributing to ion and pH homeostasis in the retina."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural and electrophysiological investigations indicate that bestrophins oligomerize to form channels whose gating is tightly regulated by intracellular Ca²⁺ via distinct acidic and EF‐hand–like domains; disruption of these domains by pathogenic mutations can severely reduce or abolish channel currents."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its canonical role in Cl⁻ transport, BEST1 has been implicated in modulating voltage‐dependent Ca²⁺ channels in the RPE and in regulating intracellular Ca²⁺ signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Notably, BEST1 expressed in glial cells of the cerebellum facilitates tonic inhibition by directly mediating the release of γ‐aminobutyric acid (GABA) through its pore"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", suggesting that its ion transport functions extend beyond the RPE. Mutations in BEST1 underlie a spectrum of inherited retinal dystrophies—including Best vitelliform macular dystrophy and autosomal recessive bestrophinopathy—by impairing channel function, altering ion permeability, or disturbing channel gating."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish BEST1 as a multifunctional channel that not only orchestrates Cl⁻ (and possibly HCO₃⁻) flux in the RPE and neural tissues, but also modulates Ca²⁺ signaling and neurotransmitter release. Disruption of BEST1’s channel activity by disease‐causing mutations leads to imbalances in ion homeostasis and intracellular signaling that contribute to retinal pathology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hui Sun, Takashi Tsunenari, King-Wai Yau, et al. 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