Malignant hyperthermia (MH) susceptibility has been attributed to a leaky sarcoplasmic reticulum (SR) caused by missense mutations in RYR1 or CACNA1S, and the MH crisis has been attributed solely to massive self-sustaining release of Ca from SR stores elicited by triggering agents. Here, we show in muscle cells from MH-RyR1 knock-in mice that increased passive SR Ca leak causes an enlarged basal influx of sarcolemmal Ca that results in chronically elevated myoplasmic free Ca concentration (Ca) at rest. We discovered that Gd and GsMTx-4 were more effective than BTP2 or expression of the dominant-negative Orai1 in reducing both Ca entry and Ca, implicating a non-STIM1/Orai1 SOCE pathway in resetting resting Ca. Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and Na is chronically elevated in MH-RyR1 muscle cells. Ca and Na are persistently elevated in vivo and further increased by halothane in MH-RyR1 muscle. These increases are markedly attenuated by local perfusion of Gd or GsMTx-4 and completely suppressed by dantrolene. These results contribute a new paradigm for understanding MH pathophysiology by demonstrating that nonselective sarcolemmal cation channel activity plays a critical role in causing myoplasmic Ca and Na overload both at rest and during the MH crisis.
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