ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2013
Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 83 citations in OpenAlex.
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- A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.Nature communications · 2021Article
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- Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.Anesthesiology · 2021Article
- The Orai1 inhibitor BTP2 has multiple effects on Ca2+ handling in skeletal muscle.The Journal of general physiology · 2021Article
- T lymphocytes from malignant hyperthermia-susceptible mice display aberrations in intracellular calcium signaling and mitochondrial function.Cell calcium · 2021Article
- Physiological and Pathological Relevance of Selective and Nonselective CaAdvances in experimental medicine and biology · 2021Article
- Effects of Naringin on Cardiomyocytes From a Rodent Model of Type 2 Diabetes.Frontiers in pharmacology · 2021Article
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Authors and funding
5 authors at 3 institutions in 1 country.
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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.
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