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Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia
Author(s) -
Eltit José M.,
Ding Xudong,
Pessah Isaac N.,
Allen Paul D.,
Lopez José R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-218354
Subject(s) - malignant hyperthermia , trpc3 , chemistry , dantrolene , endocrinology , pathogenesis , medicine , endoplasmic reticulum , ryr1 , ryanodine receptor , calcium , pathology , biochemistry , transient receptor potential channel , receptor , trpc
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. FASEB J. 27, 991–1000 (2013). www.fasebj.org