title: Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor.
abstract: Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca(2+) release in skeletal muscle and a potentially fatal rise in perioperative body temperature. Mutations causing MH susceptibility have been identified in two proteins critical for excitation-contraction (EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca(V)1.1, the principal subunit of the L-type Ca(2+) channel. All of the mutations that have been characterized previously augment EC coupling and/or increase the rate of L-type Ca(2+) entry. The Ca(V)1.1 mutation R174W associated with MH susceptibility occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca(V) channels [Carpenter D, et al. (2009) BMC Med Genet 10:104-115.]. To define the functional consequences of this mutation, we expressed it in dysgenic (Ca(V)1.1 null) myotubes. Unlike previously described MH-linked mutations in Ca(V)1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca(2+) release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca(V)1.1 R174W-expressing myotubes, resting myoplasmic Ca(2+) levels were elevated, and sarcoplasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca(V)1.1. Our results indicate that Ca(V)1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyR1-mediated Ca(2+) leak from the SR, and that perturbation of Ca(V)1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Eltit
authors.forename: Roger A
authors.initials: RA
authors.lastname: Bannister
authors.forename: Ong
authors.initials: O
authors.lastname: Moua
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hopkins
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Tadeusz F
authors.initials: TF
authors.lastname: Molinski
authors.forename: Jose R
authors.initials: JR
authors.lastname: López
authors.forename: Kurt G
authors.initials: KG
authors.lastname: Beam
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
mesh_terms: D000704:Analysis of Variance; D000777:Anesthetics / Q000494:pharmacology; D001831:Body Temperature; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D056966:Excitation Contraction Coupling / Q000235:genetics / Q000502:physiology*; D005453:Fluorescence; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics*; D008839:Microelectrodes; D018482:Muscle, Skeletal / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D000777:Anesthetics; C495540:CAV1 protein, human; D051242:Caveolin 1; D018076:DNA, Complementary; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium