{"doi":"10.1113/jp288499","title":"Catecholaminergic polymorphic ventricular tachycardia–linked ryanodine receptor variants exhibit domain‐specific calcium leak and calmodulin affinity properties","abstract":"Abstract Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress‐induced arrhythmogenic disease often caused by point variants in the cardiac ryanodine receptor (RyR2) that enhance diastolic sarcoplasmic reticulum (SR) Ca 2+ leak. These RyR2 variants cluster in three hot‐spots (N‐terminal, central and C‐terminal domains). We previously demonstrated a pathologic diastolic RyR2 conformation in heart failure, oxidative stress and CaMKII phosphorylation exhibiting a trilogy of effects: (1) reduced calmodulin (CaM)‐RyR2 affinity, (2) enhanced unzipping peptide (DPc10) binding and (3) elevated diastolic SR Ca 2+ leak that are dantrolene‐sensitive. Here we test whether this pathological trilogy occurs in CPVT knock‐in (KI) mice bearing N‐terminal (R176Q/+), central (R2474S/+) and C‐terminal variants (R4496C/+). Isolated saponin‐permeabilized ventricular myocytes from all three KI mice exhibited unaltered baseline CaM and DPc10 binding to RyR2 versus wild‐type (WT) myocytes. However cAMP‐induced protein kinase A (PKA)‐dependent RyR2 phosphorylation revealed the pathological trilogy, but only in R176Q and R2474S KI myocytes. That contrasts with WT and R4496C KI myocytes where cAMP enhanced SR Ca 2+ leak without altering either CaM‐ or DPc10‐RyR2 affinity. We conclude that CPVT‐linked RyR2 variants at baseline may not exhibit the pathological diastolic trilogy above, but that trilogy is induced by PKA activation only in N‐terminal and central domain CPVT variants. Thus the mechanism of arrhythmogenic RyR2 leak in pore domain variants (e.g. R4496C) may not involve the same pathological conformational changes as in N‐terminal and central domain variants. This may inform which specific CPVT‐linked RyR2 variants may benefit from therapeutic strategies that target this pathological trilogy conformation. image Key points We tested whether CPVT‐linked RyR2 variants in the N‐terminal (R176Q/+), central (R2474S/+) and C‐terminal/pore (R4496C/+) domains mimic a pathologic trilogy of reduced CaM affinity, enhanced DPc10 peptide binding and arrhythmogenic leaky RyR2. At baseline, none of these RyR2 variant knock‐in ventricular myocytes exhibited the above trilogy that is seen with heart failure, oxidative stress and CaMKII activation. However PKA activation by cAMP promotes that pathological trilogy, but only in the N‐terminal and central domain variant myocytes, not the pore domain variant. Targeted therapies may need to be different for different CPVT‐linked variants.","journal":"The Journal of Physiology","year":2025,"id":530077,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9661,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":917147,"name":"Xiaoqiong Dong","orcid":null,"position":1,"is_corresponding":false},{"id":1409425,"name":"Ivanita Stefanon","orcid":"0000-0003-2638-5183","position":2,"is_corresponding":false},{"id":314322,"name":"Yi Yang","orcid":"0000-0003-1491-8106","position":3,"is_corresponding":false},{"id":1409426,"name":"Eduardo Hertel Ribeiro","orcid":"0000-0002-9725-3869","position":4,"is_corresponding":false},{"id":430804,"name":"Bengt Svensson","orcid":"0000-0003-3932-2376","position":5,"is_corresponding":false},{"id":298615,"name":"Xander H.T. Wehrens","orcid":"0000-0001-5044-672X","position":6,"is_corresponding":false},{"id":1409427,"name":"Takeshi Yamamoto","orcid":"0000-0001-9334-5478","position":7,"is_corresponding":false},{"id":417548,"name":"Rǎzvan L. Cornea","orcid":"0000-0001-5739-0992","position":8,"is_corresponding":false},{"id":417546,"name":"Robyn T. Rebbeck","orcid":"0000-0003-3840-2286","position":9,"is_corresponding":false},{"id":1409428,"name":"Masafumi Yano","orcid":"0000-0001-7425-1820","position":10,"is_corresponding":false},{"id":229037,"name":"Donald M. Bers","orcid":"0000-0002-2237-9483","position":11,"is_corresponding":false},{"id":542858,"name":"Hitoshi Uchinoumi","orcid":"0000-0002-5704-3576","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:51:01.235017Z","pmid":"40320903","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}