Pharmacologic and Functional Characterization of Malignant Hyperthermia in the R163C RyR1 Knock-in Mouse

Yang, Tianzhong; Riehl, Joyce; Estève, É.; Matthaei, Klaus I.; Goth, Samuel R.; Allen, Paul D.; Pessah, Isaac N.; López, José R.

doi:10.1097/00000542-200612000-00016

Cited by 133 publications

(213 citation statements)

References 37 publications

(50 reference statements)

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“…2 G and H). As would be expected for MH-susceptible muscle (10,29), Ca V 1.1 R174W-expressing myotubes were more sensitive to caffeine (EC 50 = 2.6 ± 0.2 mM, n = 28) than myotubes expressing Ca V 1.1 (EC 50 = 4.8 ± 0.4 mM, n = 24; P < 0.001, t test; Fig. 2I).…”

Section: Resultssupporting

confidence: 71%

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Eltit

Bannister²,

Moua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Resultssupporting

confidence: 71%

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Eltit

Bannister²,

Moua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…They were further divided into several small bundles of four to six muscle fibers for the Ca 2ϩ measurements. (ii) In vitro, Flexor digitorum brevis (FDB) muscle fibers from 3-4-month-old C57BL/6 MHN and congenic heterozygous RYR1 R163C C57BL/6 MHS mice (29) were obtained by enzymatic digestion. FDB muscles were incubated with 400 units/ml of collagenase type 2 (Worthington, Lakewood, NJ) in DMEM supplemented with penicillin/streptomycin (1 time) for 90 min at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Altamirano

Eltit

Robin

et al. 2014

Journal of Biological Chemistry

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“…These include two mouse lines with leaky MH/CCD mutations R163C (17) and Y522S (18). We generated a KI mouse line (19) carrying the EC-uncoupling RyR1 mutation, I4895T, which corresponds to one of the most common CCD mutations in human RYR1, I4898T (11).…”

mentioning

confidence: 99%

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

Zvaritch

Kraeva

Bombardier

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Ryr1 I4895T/wt (IT/؉) mice express a knockin mutation corresponding to the human I4898T EC-uncoupling mutation in the type 1 ryanodine receptor/Ca 2؉ release channel (RyR1), which causes a severe form of central core disease (CCD). IT/؉ mice exhibit a slowly progressive congenital myopathy, with neonatal respiratory stress, skeletal muscle weakness, impaired mobility, dorsal kyphosis, and hind limb paralysis. Lesions observed in myofibers from diseased mice undergo age-dependent transformation from minicores to cores and nemaline rods. Early ultrastructural abnormalities include sarcomeric misalignment, Z-line streaming, focal loss of cross-striations, and myofibrillar splitting and intermingling that may arise from defective myofibrillogenesis. However, manifestation of the disease phenotype is highly variable on a Sv129 genomic background. Quantitative RT-PCR shows an equimolar ratio of WT and mutant Ryr1 transcripts within IT/؉ myofibers and total RyR1 protein expression levels are normal. We propose a unifying theory in which the cause of core formation lies in functional heterogeneity among RyR1 tetramers. Random combinations of normal and either leaky or EC-uncoupled RyR subunits would lead to spatial differences in Ca 2؉ transients; the resulting heterogeneity of contraction among myofibrils would lead to focal, irreversible tearing and shearing, which would, over time, enlarge to form minicores, cores, and nemaline rods. The IT/؉ mouse line is proposed to be a valid model of RyR1-related congenital myopathy, offering high potential for elucidation of the pathogenesis of skeletal muscle disorders arising from impaired EC coupling.calcium ͉ central core disease ͉ multiminicore disease ͉ nemaline rod myopathy ͉ ryanodine receptor

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Pharmacologic and Functional Characterization of Malignant Hyperthermia in the R163C RyR1 Knock-in Mouse

Abstract: Heterozygous R163C mice represent a valid model for studying the mechanisms that cause the human malignant hyperthermia syndrome.

Cited by 133 publications

References 37 publications

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

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Pharmacologic and Functional Characterization of Malignant Hyperthermia in the R163C RyR1 Knock-in Mouse

Abstract: Heterozygous R163C mice represent a valid model for studying the mechanisms that cause the human malignant hyperthermia syndrome.

Cited by 133 publications

References 37 publications

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca 2+ channel and the type 1 ryanodine receptor

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca 2+ channel and the type 1 ryanodine receptor

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

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Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca ²⁺ channel and the type 1 ryanodine receptor

Ca ²⁺ dysregulation in Ryr1 ^I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods