{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T02:19:31Z","timestamp":1787192371753,"version":"build-2736575974"},"reference-count":57,"publisher":"Rockefeller University Press","issue":"3","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/rupress.org\/pages\/terms102024"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AR074985"],"award-info":[{"award-number":["AR074985"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1F30AR081675"],"award-info":[{"award-number":["1F30AR081675"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,5]]},"abstract":"<jats:p>Patients with periodic paralysis have attacks of weakness precipitated by depolarization of muscle. Each form of periodic paralysis is associated with unique changes in serum K+ during attacks of weakness. In hypokalemic periodic paralysis (hypoKPP), the mutation-induced gating pore current causes weakness associated with low serum K+. In hyperkalemic periodic paralysis (hyperKPP), mutations increase a non-inactivating Na+ current (Na persistent or NaP), which causes weakness associated with elevation of extracellular K+. In Andersen\u2013Tawil syndrome, mutations causing loss of Kir channel function cause weakness associated with either low or high K+. We developed a computer model to address two questions: (1) What mechanisms are responsible for the distinct K+ dependencies of muscle depolarization-induced weakness in the three forms of periodic paralysis? (2) Why does extracellular K+ become elevated during attacks of weakness in hyperKPP, reduced in hypoKPP, and both elevated and reduced in Andersen\u2013Tawil syndrome? We experimentally tested the model assumptions about resting potential in normal K+ solution in hyperKPP and hypoKPP. Recreating the distinct K+ dependence of all three forms of periodic paralysis required including the K+ and voltage dependence of current through Kir channels, the extracellular K+ and intracellular Na+ dependence of the Na\/K ATPase activity, and the distinct voltage dependencies of the gating pore current and NaP. A key factor determining whether muscle would depolarize was the direction of small net K+ and net Na+ fluxes, which altered ion concentrations over hours. Our findings may aid in development of novel therapy for diseases with dysregulation of muscle excitability.<\/jats:p>","DOI":"10.1085\/jgp.202413610","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T02:20:33Z","timestamp":1737080433000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanisms underlying the distinct K+ dependencies of periodic paralysis"],"prefix":"10.1085","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-5049","authenticated-orcid":true,"given":"Brent D.","family":"Foy","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Wright State University 1 Department of Physics, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0249-9151","authenticated-orcid":true,"given":"Chris","family":"Dupont","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Physiology, Wright State University 2 Department of Neuroscience, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6876-2300","authenticated-orcid":true,"suffix":"II","given":"Phillip V.","family":"Walker","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Physiology, Wright State University 2 Department of Neuroscience, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6441-8882","authenticated-orcid":true,"given":"Kirsten","family":"Denman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Physiology, Wright State University 2 Department of Neuroscience, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1058-5343","authenticated-orcid":true,"given":"Kathrin L.","family":"Engisch","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Physiology, Wright State University 2 Department of Neuroscience, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-5531","authenticated-orcid":true,"given":"Mark M.","family":"Rich","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qk6pt94","id-type":"ROR","asserted-by":"publisher"}],"name":"Cell Biology and Physiology, Wright State University 2 Department of Neuroscience, , Dayton, OH,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"2025020414473324900_bib1","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1113\/jphysiol.1989.sp017582","article-title":"Intracellular chloride and the mechanism for its accumulation in rat lumbrical muscle","volume":"411","author":"Aickin","year":"1989","journal-title":"J. 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