New abstract on the sarcolemmal cation channel announced

Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia. link to PubMed article.

Eltit JM, Ding X, Pessah IN, Allen PD, Lopez JR. Source *Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA;

Abstract 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(2+) from SR stores elicited by triggering agents. Here, we show in muscle cells from MH-RyR1(R163C) knock-in mice that increased passive SR Ca(2+) leak causes an enlarged basal influx of sarcolemmal Ca(2+) that results in chronically elevated myoplasmic free Ca(2+) concentration ([Ca(2+)](i)) at rest. We discovered that Gd(+3) and GsMTx-4 were more effective than BTP2 or expression of the dominant-negative Orai1(E190Q) in reducing both Ca(2+) entry and [Ca(2+)](i), implicating a non-STIM1/Orai1 SOCE pathway in resetting resting [Ca(2+)](i). Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and [Na](i) is chronically elevated in MH-RyR1(R163C) muscle cells. [Ca(2+)](i) and [Na(+)](i) are persistently elevated in vivo and further increased by halothane in MH-RyR1(R163C/WT) muscle. These increases are markedly attenuated by local perfusion of Gd(+3) 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(2+) and Na(+) overload both at rest and during the MH crisis.-Eltit, J. M., Ding, X., Pessah, I. N., Allen, P. D., Lopez, J. R. Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia.