title: Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia.
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.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Eltit
authors.forename: Xudong
authors.initials: X
authors.lastname: Ding
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
authors.forename: José R
authors.initials: JR
authors.lastname: Lopez
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D002413:Cations, Divalent / Q000378:metabolism; D002414:Cations, Monovalent / Q000378:metabolism; D008305:Malignant Hyperthermia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D000071740:ORAI1 Protein; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1
chemical_list: C529218:CACNA1S protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002413:Cations, Divalent; D002414:Cations, Monovalent; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D012964:Sodium; D002118:Calcium