{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:24:02Z","timestamp":1791480242943,"version":"4.3.4"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,10]]},"abstract":"\n Normal resting potential (P1) of myofibers follows the Nernst equation, exhibiting about \u221285 mV at a normal extracellular K\n +<\/jats:sup>\n concentration ([K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n ) of 4 mM. Hyperpolarization occurs with decreased [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n , although at [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n < 1.0 mM, myofibers paradoxically depolarize to a second stable potential of \u221260 mV (P2). In rat myofiber bundles, P2 also was found at more physiological [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n and was associated with inexcitability. To increase the relative frequency of P2 to 50%, [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n needed to be lowered to 1.5 mM. In the presence of the ionophore gramicidin, [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n reduction to only 2.5 mM yielded the same effect. Acetazolamide normalized this increased frequency of P2 fibers. The findings mimic hypokalemic periodic paralysis (HypoPP), a channelopathy characterized by hypokalemia-induced weakness. Of myofibers from 7 HypoPP patients, up to 25% were in P2 at a [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n of 4 mM, in accordance with their permanent weakness, and up to 99% were in P2 at a [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n of 1.5 mM, in accordance with their paralytic attacks. Of 36 HypoPP patients, 25 had permanent weakness and myoplasmic intracellular Na\n +<\/jats:sup>\n ([Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n ) overload (up to 24 mM) as shown by in vivo\n 23<\/jats:sup>\n Na-MRI. Acetazolamide normalized [Na\n +<\/jats:sup>\n ]\n i<\/jats:sub>\n and increased muscle strength. HypoPP myofibers showed a nonselective cation leak of 12\u201319.5 \u03bcS\/cm\n 2<\/jats:sup>\n , which may explain the Na\n +<\/jats:sup>\n overload. The leak sensitizes myofibers to reduced serum K\n +<\/jats:sup>\n , and the resulting membrane depolarization causes the weakness. We postulate that the principle of paradoxical depolarization and loss of function upon [K\n +<\/jats:sup>\n ]\n o<\/jats:sub>\n reduction may apply to other tissues, such as heart or brain, when they become leaky (e.g., because of ischemia).\n <\/jats:p>","DOI":"10.1073\/pnas.0811277106","type":"journal-article","created":{"date-parts":[[2009,2,18]],"date-time":"2009-02-18T21:40:55Z","timestamp":1234993255000},"page":"4036-4041","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":152,"title":["K\n +<\/sup>\n -dependent paradoxical membrane depolarization and Na\n +<\/sup>\n overload, major and reversible contributors to weakness by ion channel leaks"],"prefix":"10.1073","volume":"106","author":[{"given":"Karin","family":"Jurkat-Rott","sequence":"first","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-Andr\u00e9","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Fauler","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu-Hai","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris D.","family":"Holzherr","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, Ulm, 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