{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The KCNK18 gene encodes the two‐pore domain potassium channel TRESK, a background (“leak”) K⁺ channel that plays a critical role in setting the resting membrane potential and modulating cellular excitability. In sensory neurons, particularly in the trigeminal and dorsal root ganglia, TRESK provides an important inhibitory influence on neuronal firing, and loss‐of‐function mutations (such as the frameshift F139WfsX24 mutation) cause a dominant‐negative effect that enhances neuronal excitability and has been strongly linked to migraine with aura."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Cloning and electrophysiological studies confirmed that TRESK functions as a background K⁺ channel in the spinal cord and other excitable cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while detailed analyses have demonstrated that its activity is regulated by calcium‐dependent signaling via calcineurin, with specific docking sites (including PQIIIS and LQLP motifs) and modulatory interactions with 14–3–3 proteins fine‐tuning its kinetics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": " Species-specific properties, including pH sensitivity and posttranslational modifications like glycosylation, further contribute to the nuanced control of TRESK channel function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition to its role in neuronal excitability and migraine pathogenesis—as reviewed in several studies"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "—TRESK has been implicated in other physiological functions. For example, TRESK contributes to the background K⁺ currents that underlie regulatory volume decrease in T lymphocytes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and is expressed in lymphoblastic cells, suggesting a potential role in cell proliferation and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Furthermore, in human induced pluripotent stem cell–derived nociceptors, TRESK loss caused by migraine-associated mutations increases neuronal firing, and pharmacological activation by agents such as cloxyquin can reduce hyperexcitability"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while high-throughput screening has identified selective modulators of KCNK18/TRESK activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Structural studies have provided insights into TRESK’s channel architecture and key ligand–channel interactions that may guide future drug design."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Finally, genetic analyses in various populations indicate that although rare loss‐of‐function variants clearly impact migraine susceptibility"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", common polymorphisms in KCNK18 do not appear to have a significant effect. Notably, emerging evidence also suggests a role for TRESK in modulating network excitability in epilepsy via depolarization-induced shunting inhibition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Collectively, these studies underscore that TRESK, encoded by KCNK18, is a key regulator of cellular excitability in both neuronal and non-neuronal tissues, representing a promising therapeutic target for migraine, pain disorders, and potentially other conditions.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Additional network analyses have linked TRESK function to other migraine risk factors and ion channel interactions, further emphasizing its importance in neurophysiological homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ronald G Lafrenière, M Zameel Cader, Jean-François Poulin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2216"}], "href": "https://doi.org/10.1038/nm.2216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20871611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20871611"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhaohua Guo, Ping Liu, Fei Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurophysiol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/jn.00267.2014"}], "href": "https://doi.org/10.1152/jn.00267.2014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24805079"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24805079"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yorikata Sano, Kohei Inamura, Akira Miyake, et al. 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