{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T21:12:16Z","timestamp":1785013936868,"version":"3.55.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>The cardiac ryanodine receptor Ca<jats:sup>2+<\/jats:sup> release channel (RyR2) is inserted into the membrane of intracellular sarcoplasmic reticulum (SR) myocyte Ca<jats:sup>2+<\/jats:sup> stores, where it releases the Ca<jats:sup>2+<\/jats:sup> essential for contraction. Mutations in proteins involved in Ca<jats:sup>2+<\/jats:sup> signaling can lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). The most common cellular phenotype in CPVT is higher than normal cytoplasmic Ca<jats:sup>2+<\/jats:sup> concentrations during diastole due to Ca<jats:sup>2+<\/jats:sup> leak from the SR through mutant RyR2. Arrhythmias are triggered when the surface membrane sodium calcium exchanger (NCX) lowers cytoplasmic Ca<jats:sup>2+<\/jats:sup> by importing 3 Na<jats:sup>+<\/jats:sup> ions to extrude one Ca<jats:sup>2+<\/jats:sup> ion. The Na<jats:sup>+<\/jats:sup> influx leads to delayed after depolarizations (DADs) which trigger arrhythmia when reaching action potential threshold. Present therapies use drugs developed for different purposes that serendipitously reduce RyR2 Ca<jats:sup>2+<\/jats:sup> leak, but can adversely effect systolic Ca<jats:sup>2+<\/jats:sup> release and other target processes. Ideal drugs would specifically reverse the effect of individual mutations, without altering normal channel function. Such drugs will depend on the location of the mutation in the 4967-residue monomer and the effect of the mutation on local structure, and downstream effects on structures along the conformational pathway to the pore. Such atomic resolution information is only now becoming available. This perspective provides a summary of known or predicted structural changes associated with a handful of CPVT mutations. Known molecular changes associated with RyR opening are discussed, as well one study where minute molecular changes with a particular mutation have been tracked from the N-terminal mutation site to gating residues in the channel pore.<\/jats:p>","DOI":"10.3389\/fphys.2022.830367","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T10:03:41Z","timestamp":1644487421000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)"],"prefix":"10.3389","volume":"13","author":[{"given":"Angela F.","family":"Dulhunty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm7110423","article-title":"Post-translational modifications and diastolic calcium leak associated to the novel RyR2-D3638A mutation lead to CPVT in patient-specific hiPSC-derived cardiomyocytes.","volume":"7","author":"Acimovic","year":"2018","journal-title":"J. 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