{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:14:56Z","timestamp":1791029696567,"version":"4.1.0"},"reference-count":61,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,6,1]]},"abstract":"<jats:p>Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation\u2013contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Hom) RYR1-R163C knock-in mouse myotubes to maintained K+ depolarization. The new findings are: (a) For all three genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT &amp;gt; Het &amp;gt; Hom. (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes. (d) When Ca2+ entry is blocked, the decay rates are slower for Hom and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT &amp;gt; Het &amp;gt; Hom). (e) Reduced ECC inactivation in Het and Hom myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor.<\/jats:p>","DOI":"10.1085\/jgp.200910328","type":"journal-article","created":{"date-parts":[[2010,5,18]],"date-time":"2010-05-18T03:25:27Z","timestamp":1274153127000},"page":"619-628","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["A malignant hyperthermia\u2013inducing mutation in RYR1 (R163C): alterations in Ca2+ entry, release, and retrograde signaling to the DHPR"],"prefix":"10.1085","volume":"135","author":[{"given":"Eric","family":"Est\u00e8ve","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115 1"},{"name":"Universit\u00e9 Victor Segalen Bordeaux 2, Institut National de la Sant\u00e9 et de la Recherche Medicale U885, Laboratoire de Physiologie Cellulaire Respiratoire, 33076 Bordeaux, France 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Eltit","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115 1"},{"name":"Programa de Biologia Molecular y Celular, Instituto de Ciencias Biomedicas Facultad de Medicina, Universidad de Chile, Casilla 70005, Santiago, Chile 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger A.","family":"Bannister","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac N.","family":"Pessah","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA 95616 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt G.","family":"Beam","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 R.","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2010,5,17]]},"reference":[{"key":"2023072622003607900_bib1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1113\/jphysiol.1981.sp013622","article-title":"Slow calcium and potassium currents across frog muscle membrane: measurements with a vaseline-gap technique","volume":"312","author":"Almers","year":"1981","journal-title":"J. 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