{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:33:29Z","timestamp":1792737209108,"version":"4.5.0"},"reference-count":29,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:p>In skeletal muscle, slow inactivation (SI) of NaV1.4 voltage-gated sodium channels prevents spontaneous depolarization and fatigue. Inherited mutations in NaV1.4 that impair SI disrupt activity-induced regulation of channel availability and predispose patients to hyperkalemic periodic paralysis. In our companion paper in this issue (Silva and Goldstein. 2013. J. Gen. Physiol. http:\/\/dx.doi.org\/10.1085\/jgp.201210909), the four voltage sensors in NaV1.4 responsible for activation of channels over microseconds are shown to slowly immobilize over 1\u2013160 s as SI develops and to regain mobility on recovery from SI. Individual sensor movements assessed via attached fluorescent probes are nonidentical in their voltage dependence, time course, and magnitude: DI and DII track SI onset, and DIII appears to reflect SI recovery. A causal link was inferred by tetrodotoxin (TTX) suppression of both SI onset and immobilization of DI and DII sensors. Here, the association of slow sensor immobilization and SI is verified by study of NaV1.4 channels with a hyperkalemic periodic paralysis mutation; L689I produces complex changes in SI, and these are found to manifest directly in altered sensor movements. L689I removes a component of SI with an intermediate time constant (\u223c10 s); the mutation also impedes immobilization of the DI and DII sensors over the same time domain in support of direct mechanistic linkage. A model that recapitulates SI attributes responsibility for intermediate SI to DI and DII (10 s) and a slow component to DIII (100 s), which accounts for residual SI, not impeded by L689I or TTX.<\/jats:p>","DOI":"10.1085\/jgp.201210910","type":"journal-article","created":{"date-parts":[[2013,2,12]],"date-time":"2013-02-12T04:03:51Z","timestamp":1360641831000},"page":"323-334","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: A periodic paralysis mutation in NaV1.4 (L689I)"],"prefix":"10.1085","volume":"141","author":[{"given":"Jonathan R.","family":"Silva","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Brandeis University, Waltham, MA 02453"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve A.N.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Brandeis University, Waltham, MA 02453"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,2,11]]},"reference":[{"key":"2023072622383533700_bib1","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1161\/CIRCULATIONAHA.106.668392","article-title":"Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death","volume":".115","author":"Antzelevitch","year":"2007","journal-title":"Circulation"},{"key":"2023072622383533700_bib2","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1113\/jphysiol.1996.sp021503","article-title":"External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels","volume":"494","author":"Balser","year":"1996","journal-title":"J. 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