{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KCNS1 encodes the “silent” voltage‐gated potassium channel α‐subunit Kv9.1, which, although unable to form functional channels by itself, modulates the properties of co‐assembled partner subunits (e.g., Kv2.1) to fine‐tune neuronal excitability. In sensory neurons, KCNS1 is constitutively expressed and its downregulation following nerve injury is associated with heightened pain sensitivity; genetic studies have further implicated specific KCNS1 variants—such as the valine risk allele—in increasing susceptibility to chronic neuropathic and postsurgical pain conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Variations in KCNS1 have also been linked to preoperative pain in breast cancer patients"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and to altered pain intensity in HIV-associated sensory neuropathy when considered as part of specific haplotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In murine models, conditional deletion of Kcns1 in peripheral sensory neurons produces modest increases in baseline mechanical pain and exaggerated hypersensitivity following neuropathic injury, underscoring its role in controlling mechanical and cold sensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " At the biophysical level, co-assembly of Kv9.1 with Kv2.1 alters channel activation and inactivation kinetics—including a negative shift in voltage dependence and a biphasic current–voltage relationship—thus impacting the ability of neurons to fire at high frequencies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, enhanced KCNS1 mRNA expression following BMP-2 stimulation in pulmonary artery smooth muscle cells suggests that its regulatory role may extend beyond neuronal excitability to the modulation of vascular tone"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while its markedly higher expression in specific subdivisions of the cochlear nucleus indicates a potential function in auditory processing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings underscore the multifaceted role of KCNS1 as a modulator of ion channel activity that influences not only neuronal firing and signal integration but also clinical pain phenotypes, thereby representing a promising target for prognostic assessment and therapeutic intervention in chronic pain syndromes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael Costigan, Inna Belfer, Robert S Griffin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awq195"}], "href": "https://doi.org/10.1093/brain/awq195"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20724292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20724292"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Vidya Chidambaran, Yang Gang, Valentina Pilipenko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Systematic Review and Meta-Analysis of Genetic Risk of Developing Chronic Postsurgical Pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pain (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jpain.2019.05.008"}], "href": "https://doi.org/10.1016/j.jpain.2019.05.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31129315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31129315"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Daisy M N Hoofwijk, Roel R I van Reij, Bart P F Rutten, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic polymorphisms and prediction of chronic post-surgical pain after hysterectomy-a subgroup analysis of a multicenter cohort study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Anaesthesiol Scand (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/aas.13413"}], "href": "https://doi.org/10.1111/aas.13413"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31206175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31206175"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dale J Langford, Claudia West, Charles Elboim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variations in potassium channel genes are associated with breast pain in women prior to breast cancer surgery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurogenet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/01677063.2013.856430"}], "href": "https://doi.org/10.3109/01677063.2013.856430"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24392765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24392765"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Liesl Hendry, Zané Lombard, Antonia Wadley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KCNS1, but not GCH1, is associated with pain intensity in a black southern African population with HIV-associated sensory neuropathy: a genetic association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Acquir Immune Defic Syndr (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/QAI.0b013e318285cf36"}], "href": "https://doi.org/10.1097/QAI.0b013e318285cf36"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23314412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23314412"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Christoforos Tsantoulas, Franziska Denk, Massimo Signore, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pain (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/j.pain.0000000000001255"}], "href": "https://doi.org/10.1097/j.pain.0000000000001255"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29697531"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29697531"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "M Stocker, D Kerschensteiner "}, {"type": "b", "children": [{"type": "t", "text": "Cloning and tissue distribution of two new potassium channel alpha-subunits from rat brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (1998)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/bbrc.1998.9072"}], "href": "https://doi.org/10.1006/bbrc.1998.9072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9704029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9704029"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "F C Richardson, L K Kaczmarek "}, {"type": "b", "children": [{"type": "t", "text": "Modification of delayed rectifier potassium currents by the Kv9.1 potassium channel subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hear Res (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0378-5955(00)00117-9"}], "href": "https://doi.org/10.1016/s0378-5955(00"}, {"type": "t", "text": "00117-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10962170"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10962170"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ivana Fantozzi, Oleksandr Platoshyn, Ada H Wong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bone morphogenetic protein-2 upregulates expression and function of voltage-gated K+ channels in human pulmonary artery smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Lung Cell Mol Physiol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajplung.00191.2005"}], "href": "https://doi.org/10.1152/ajplung.00191.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16815889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16815889"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "David R Friedland, Rebecca Eernisse, Paul Popper "}, {"type": "b", "children": [{"type": "t", "text": "Potassium channel gene expression in the rat cochlear nucleus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hear Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.heares.2007.01.024"}], "href": "https://doi.org/10.1016/j.heares.2007.01.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17346910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17346910"}]}]}]}