ArticleProceedings of the National Academy of Sciences of the United States of America2009
A retrograde signal from RyR1 alters DHP receptor inactivation and limits window Ca2+ release in muscle fibers of Y522S RyR1 knock-in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 61 citations in OpenAlex.
- Pathogenic CaCommunications biology · 2026Article
- Stable oxidative posttranslational modifications alter the gating properties of RyR1.The Journal of general physiology · 2024Article
- Distinct pathophysiological characteristics in developing muscle from patients susceptible to malignant hyperthermia.British journal of anaesthesia · 2023Article
- Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Pannexin-1 and CaV1.1 show reciprocal interaction during excitation-contraction and excitation-transcription coupling in skeletal muscle.The Journal of general physiology · 2021Article
- Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation.Nature communications · 2020Article
- Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019.Orphanet journal of rare diseases · 2020Article
- CaCells · 2019Review
- Excessive Accumulation of CaFrontiers in physiology · 2019Article
- Role of STIM1/ORAI1-mediated store-operated CaCell calcium · 2018Review
- Voltage modulates halothane-triggered CaThe Journal of general physiology · 2018Article
- Muscle Weakness in Rheumatoid Arthritis: The Role of CaEBioMedicine · 2017Review
- Review of RyR1 pathway and associated pathomechanisms.Acta neuropathologica communications · 2016Review
- Retrograde Coupling: Muscle's Orphan Signaling Pathway?Biophysical journal · 2016Article
- Rectification of muscle and nerve deficits in paralyzed ryanodine receptor type 1 mutant embryos.Developmental biology · 2015Article
- Malignant hyperthermia: a review.Orphanet journal of rare diseases · 2015Review
- The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle.The Journal of general physiology · 2015Review
- The disorders of the calcium release unit of skeletal muscles: what have we learned from mouse models?Journal of muscle research and cell motility · 2015Review
- Critical Role of Intracellular RyR1 Calcium Release Channels in Skeletal Muscle Function and Disease.Frontiers in physiology · 2015Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Malignant hyperthermia (MH) is a life-threatening hypermetabolic condition caused by dysfunctional Ca(2+) homeostasis in skeletal muscle, which primarily originates from genetic alterations in the Ca(2+) release channel (ryanodine receptor, RyR1) of the sarcoplasmic reticulum (SR). Owing to its physical interaction with the dihydropyridine receptor (DHPR), RyR1 is controlled by the electrical potential across the transverse tubular (TT) membrane. The DHPR exhibits both voltage-dependent activation and inactivation. Here we determined the impact of an MH mutation in RyR1 (Y522S) on these processes in adult muscle fibers isolated from heterozygous RyR1(Y522S)-knock-in mice. The voltage dependence of DHPR-triggered Ca(2+) release flux was left-shifted by approximately 8 mV. As a consequence, the voltage window for steady-state Ca(2+) release extended to more negative holding potentials in muscle fibers of the RyR1(Y522S)-mice. A rise in temperature from 20 degrees to 30 degrees C caused a further shift to more negative potentials of this window (by approximately 20 mV). The activation of the DHPR-mediated Ca(2+) current was minimally changed by the mutation. However, surprisingly, the voltage dependence of steady-state inactivation of DHPR-mediated calcium conductance and release were also shifted by approximately 10 mV to more negative potentials, indicating a retrograde action of the RyR1 mutation on DHPR inactivation that limits window Ca(2+) release. This effect serves as a compensatory response to the lowered voltage threshold for Ca(2+) release caused by the Y522S mutation and represents a novel mechanism to counteract excessive Ca(2+) leak and store depletion in MH-susceptible muscle.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.