{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The KCNMA1 gene encodes the pore‐forming α subunit of large‐conductance, Ca²⁺‐ and voltage‐activated (“BK”) potassium channels that serve as key regulators of cellular excitability and diverse physiological processes. BK channels integrate intracellular Ca²⁺ signals with membrane voltage to modulate action potential duration, neurotransmitter release, and smooth muscle tone. For example, deletion of KCNMA1 results in the loss of BK currents in urinary bladder smooth muscle, leading to enhanced spontaneous and nerve‐evoked contractions that underlie overactive bladder symptoms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In neurons, BK channel activity is critical for limiting action potential broadening – a control mechanism that is dysregulated in fragile X syndrome through loss of FMRP’s modulation of BK channel β4 subunits"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and for maintaining appropriate spontaneous firing in the suprachiasmatic nucleus, where BK channels contribute to circadian pacemaker output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Structural studies have revealed that the intracellular “gating ring” of BK channels contains tandem regulator of K⁺ conductance (RCK) domains with multiple Ca²⁺ binding sites, providing insight into the molecular basis for channel regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " BK channels are also subject to modulation by metabolic and signaling molecules; leptin rapidly activates BK channels in hippocampal neurons to inhibit excitability"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while adenosine‐monophosphate–activated protein kinase (AMPK) and carbon monoxide can directly influence BK channel gating in O₂‐sensing cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the kidney, BK channels expressed in the aldosterone‐sensitive distal nephron mediate flow‐induced K⁺ secretion, complementing ROMK‐dependent K⁺ handling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Vascular smooth muscle BK channel activity can be suppressed by c‐Src–dependent phosphorylation, thereby contributing to agonist‐induced vasoconstriction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In addition, amplification of KCNMA1 in prostate cancer correlates with increased channel expression and contributes to enhanced cell proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", while in myometrial cells, BK channels are organized into caveolar complexes with the actin cytoskeleton to finely regulate uterine contractility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Finally, epigenetic mechanisms that silence KCNMA1 expression following nerve injury have been implicated in the pathogenesis of neuropathic pain, and BK channels also participate in shaping membrane potential oscillations in immune cells such as macrophages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Collectively, these findings underscore the central role of KCNMA1-encoded BK channels as integrators of Ca²⁺ and voltage signals and as pivotal targets for modulating cell excitability across neuronal, smooth muscle, renal, vascular, and other tissues.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrea L Meredith, Kevin S Thorneloe, Matthias E Werner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M405621200"}], "href": "https://doi.org/10.1074/jbc.M405621200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15184377"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15184377"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Pan-Yue Deng, Ziv Rotman, Jay A Blundon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2012.12.018"}], "href": "https://doi.org/10.1016/j.neuron.2012.12.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23439122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23439122"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Andrea L Meredith, Steven W Wiler, Brooke H Miller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Neurosci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nn1740"}], "href": "https://doi.org/10.1038/nn1740"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16845385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16845385"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Peng Yuan, Manuel D Leonetti, Alexander R Pico, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1190414"}], "href": "https://doi.org/10.1126/science.1190414"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20508092"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20508092"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xiang Dong Tang, Rong Xu, Mark F Reynolds, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature02003"}], "href": "https://doi.org/10.1038/nature02003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14523450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14523450"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "L J Shanley, D O'Malley, A J Irving, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2002.029488"}], "href": "https://doi.org/10.1113/jphysiol.2002.029488"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12482897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12482897"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christopher N Wyatt, Kirsty J Mustard, Selina A Pearson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AMP-activated protein kinase mediates carotid body excitation by hypoxia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M608742200"}], "href": "https://doi.org/10.1074/jbc.M608742200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17179156"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17179156"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Shangwei Hou, Rong Xu, Stefan H Heinemann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0800304105"}], "href": "https://doi.org/10.1073/pnas.0800304105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18316727"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18316727"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "T Rieg, V Vallon, M Sausbier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of the BK channel in potassium homeostasis and flow-induced renal potassium excretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ki.5002369"}], "href": "https://doi.org/10.1038/sj.ki.5002369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17579662"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17579662"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "M A Bailey, A Cantone, Q Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter's syndrome and in adaptation to a high-K diet."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ki.5000388"}], "href": "https://doi.org/10.1038/sj.ki.5000388"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16710355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16710355"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Abderrahmane Alioua, Aman Mahajan, Kazuhide Nishimaru, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Coupling of c-Src to large conductance voltage- and Ca2+-activated K+ channels as a new mechanism of agonist-induced vasoconstriction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.222348099"}], "href": "https://doi.org/10.1073/pnas.222348099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12391293"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12391293"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "M Bloch, J Ousingsawat, R Simon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1210036"}], "href": "https://doi.org/10.1038/sj.onc.1210036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17146446"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17146446"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Adam M Brainard, Andrea J Miller, Jeffrey R Martens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00399.2004"}], "href": "https://doi.org/10.1152/ajpcell.00399.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15703204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15703204"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Geoffroy Laumet, Judit Garriga, Shao-Rui Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Neurosci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nn.4165"}], "href": "https://doi.org/10.1038/nn.4165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26551542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26551542"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Peter J Hanley, Boris Musset, Vijay Renigunta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0400733101"}], "href": "https://doi.org/10.1073/pnas.0400733101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15194822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15194822"}]}]}]}