{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T12:14:53Z","timestamp":1791029693544,"version":"4.1.0"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,17]]},"abstract":"\n Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition caused by dysfunctional Ca\n 2+<\/jats:sup>\n homeostasis in skeletal muscle, which primarily originates from genetic alterations in the Ca\n 2+<\/jats:sup>\n release channel (ryanodine receptor, RyR1) of the sarcoplasmic reticulum (SR). Owing to its physical interaction with the dihydropyridine receptor (DHPR), RyR1 is controlled by the electrical potential across the transverse tubular (TT) membrane. The DHPR exhibits both voltage-dependent activation and inactivation. Here we determined the impact of an MH mutation in RyR1 (Y522S) on these processes in adult muscle fibers isolated from heterozygous RyR1\n Y522S<\/jats:sup>\n -knock-in mice. The voltage dependence of DHPR-triggered Ca\n 2+<\/jats:sup>\n release flux was left-shifted by \u22488 mV. As a consequence, the voltage window for steady-state Ca\n 2+<\/jats:sup>\n release extended to more negative holding potentials in muscle fibers of the RyR1\n Y522S<\/jats:sup>\n -mice. A rise in temperature from 20\u00b0 to 30 \u00b0C caused a further shift to more negative potentials of this window (by \u224820 mV). The activation of the DHPR-mediated Ca\n 2+<\/jats:sup>\n current was minimally changed by the mutation. However, surprisingly, the voltage dependence of steady-state inactivation of DHPR-mediated calcium conductance and release were also shifted by \u224810 mV to more negative potentials, indicating a retrograde action of the RyR1 mutation on DHPR inactivation that limits window Ca\n 2+<\/jats:sup>\n release. This effect serves as a compensatory response to the lowered voltage threshold for Ca\n 2+<\/jats:sup>\n release caused by the Y522S mutation and represents a novel mechanism to counteract excessive Ca\n 2+<\/jats:sup>\n leak and store depletion in MH-susceptible muscle.\n <\/jats:p>","DOI":"10.1073\/pnas.0812661106","type":"journal-article","created":{"date-parts":[[2009,2,25]],"date-time":"2009-02-25T22:19:05Z","timestamp":1235600345000},"page":"4531-4536","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":62,"title":["A retrograde signal from RyR1 alters DHP receptor inactivation and limits window Ca\n 2+<\/sup>\n release in muscle fibers of Y522S RyR1 knock-in mice"],"prefix":"10.1073","volume":"106","author":[{"given":"Zoita","family":"Andronache","sequence":"first","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, D-89069 Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Melzer","sequence":"additional","affiliation":[{"name":"Institute of Applied Physiology, Ulm University, D-89069 Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,3,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.256.5058.789"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1999.79.4.1317"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-21"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20356"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(94)00014-5"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(199601)19:1<68::AID-MUS9>3.0.CO;2-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(199604)19:4<450::AID-MUS4>3.0.CO;2-B"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.t01-1-00507.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.3.277"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4497fje"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.073882"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1987.sp016775"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.102.3.373"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1960.sp006541"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.157990"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.2.693"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.110.4.415"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.6.2587"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1999.4210"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.02.042"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/380072a0"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.31.21913"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.115.4.467"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.2741\/dirksen"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609473103"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0704340104"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200409168"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1986.sp016008"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200308908"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0812661106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T17:25:11Z","timestamp":1649784311000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0812661106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,17]]},"references-count":29,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2009,3,17]]}},"alternative-id":["10.1073\/pnas.0812661106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0812661106","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1160075.620345","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,17]]},"assertion":[{"value":"2008-12-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-03-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}