{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Calcium homeostasis modulator 1 (CALHM1) is a voltage‐gated, Ca²⁺‐permeable plasma membrane ion channel that plays multiple crucial roles in cellular signaling. In taste bud cells, CALHM1 is indispensable for the non‐vesicular release of ATP that mediates neurotransmission for sweet, bitter, and umami taste perception; indeed, CALHM1 (in association with CALHM3) forms a fast voltage‐gated ATP‐release channel that is essential for gustatory signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the brain, CALHM1 functions as a pore‐forming Ca²⁺ channel that regulates neuronal excitability and intracellular calcium homeostasis. Its activation modulates membrane depolarization–induced Ca²⁺ influx, which in turn influences downstream signaling pathways such as the activation of ERK kinases. These Ca²⁺‐mediated responses control synaptic plasticity and memory processing, as deletion of CALHM1 results in impaired long‐term potentiation and memory flexibility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural analyses have revealed that CALHM1 forms oligomeric channels—typically as a hexamer—with four transmembrane domains and a pore large enough to allow permeation of ions and small metabolites. In addition to its intrinsic voltage-dependent gating and regulation by extracellular Ca²⁺ levels, CALHM1 gating is modulated post-translationally through reversible palmitoylation, which in turn influences its association with lipid microdomains and fine-tunes channel activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n CALHM1 also contributes to the regulation of amyloid-β (Aβ) metabolism. Through Ca²⁺-dependent mechanisms, CALHM1 activity promotes extracellular Aβ degradation by enhancing the secretion and activity of proteolytic enzymes such as insulin-degrading enzyme. Moreover, naturally occurring polymorphisms in the CALHM1 gene that reduce channel function have been linked to altered Aβ levels and, in several studies, to modifications in Alzheimer’s disease risk or age at onset."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, studies in model organisms including Caenorhabditis elegans underscore the evolutionarily conserved role of CALHM1 in regulating Ca²⁺ homeostasis and cellular excitability, highlighting its importance across species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Akiyuki Taruno, Valérie Vingtdeux, Makoto Ohmoto, et al. 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