ArticleProceedings of the National Academy of Sciences of the United States of America2001
Ryanodine receptor point mutant E4032A reveals an allosteric interaction with ryanodine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 55 citations in OpenAlex.
- Characterization of cardiac disease-associated mutations in RyR2 CaAmerican journal of physiology. Cell physiology · 2026Article
- Binding proteins of destruxin A from Metarhizium against insect cell.BMC microbiology · 2023Article
- Structural Insight Into Ryanodine Receptor Channelopathies.Frontiers in pharmacology · 2022Review
- RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation.Acta neuropathologica communications · 2021Article
- 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
- CaThe Journal of biological chemistry · 2018Article
- Regulation of the RyR channel gating by CaBiophysical reviews · 2018Review
- The structural basis of ryanodine receptor ion channel function.The Journal of general physiology · 2017Review
- Ryanodine receptor resolution revolution: Implications for InsPCell calcium · 2017Article
- Article
- The inflammatory microenvironment in MDS.Cellular and molecular life sciences : CMLS · 2015Review
- RyR1-mediated Ca2+ leak and Ca2+ entry determine resting intracellular Ca2+ in skeletal myotubes.The Journal of biological chemistry · 2010Article
- Alteration of sarcoplasmic reticulum ca release in skeletal muscle from calpain 3-deficient mice.International journal of cell biology · 2009Article
- A Ca2+-binding domain in RyR1 that interacts with the calmodulin binding site and modulates channel activity.Biophysical journal · 2006Article
- Internal structure and visualization of transmembrane domains of the RyR1 calcium release channel by cryo-EM.Nature structural & molecular biology · 2005Article
- Evidence for conformational coupling between two calcium channels.Proceedings of the National Academy of Sciences of the United States of America · 2004Article
- Ryanodine receptor regulation by intramolecular interaction between cytoplasmic and transmembrane domains.Molecular biology of the cell · 2004Article
- Ca2+ activation of RyR1 is not necessary for the initiation of skeletal-type excitation-contraction coupling.Biophysical journal · 2002Article
- Ryanodine sensitizes the cardiac Ca(2+) release channel (ryanodine receptor isoform 2) to Ca(2+) activation and dissociates as the channel is closed by Ca(2+) depletion.Proceedings of the National Academy of Sciences of the United States of America · 2001Article
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
The ryanodine receptor (RyR) family of proteins constitutes a unique type of calcium channel that mediates Ca(2+) release from endoplasmic reticulum/sarcoplasmic reticulum stores. Ryanodine has been widely used to identify contributions made by the RyR to signaling in both muscle and nonmuscle cells. Ryanodine, through binding to high- and low-affinity sites, has been suggested to block the channel pore based on its ability to induce partial conductance states and irreversible inhibition. We examined the effect of ryanodine on an RyR type 1 (RyR1) point mutant (E4032A) that exhibits a severely compromised phenotype. When expressed in 1B5 (RyR null/dyspedic) myotubes, E4032A is relatively unresponsive to stimulation by cell membrane depolarization or RyR agonists, although the full-length protein is correctly targeted to junctions and interacts with dihydropyridine receptors (DHPRs) inducing their arrangement into tetrads. However, treatment of E4032A-expressing cells with 200-500 microM ryanodine, concentrations that rapidly activate and then inhibit wild-type (wt) RyR1, restores the responsiveness of E4032A-expressing myotubes to depolarization and RyR agonists. Moreover, the restored E4032A channels remain resistant to subsequent exposure to ryanodine. In single-channel studies, E4032A exhibits infrequent (channel-open probability, P(o) < 0.005) and brief (<250 micros) gating events and insensitivity to Ca(2+). Addition of ryanodine restores Ca(2+)-dependent channel activity exhibiting full, 3/4, 1/2, and 1/4 substates. This evidence suggests that, whereas ryanodine does not occlude the RyR pore, it does bind to sites that allosterically induce substantial conformational changes in the RyR. In the case of E4032A, these changes overcome unfavorable energy barriers introduced by the E4032A mutation to restore channel function.
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