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Mutations in RYR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is associated with enhanced spontaneous Ca2+ release, which tends to occur when [Ca2+]ER reaches a threshold. Mutations lower the threshold [Ca2+]ER by increasing luminal Ca2+ sensitivity or enhancing cytosolic [Ca2+] ([Ca2+]cyt)-dependent activity. Here, to establish the mechanism relating the change in [Ca2+]cyt-dependent activity of RYR2 and the threshold [Ca2+]ER, we carried out cell-based experiments and in silico simulations. We expressed WT and CPVT-linked mutant RYR2s in HEK293 cells and measured [Ca2+]cyt and [Ca2+]ER using fluorescent Ca2+ indicators. CPVT RYR2 cells showed higher oscillation frequency and lower threshold [Ca2+]ER than WT cells. The [Ca2+]cyt-dependent activity at resting [Ca2+]cyt, Arest, was greater in CPVT mutants than in WT, and we found an inverse correlation between threshold [Ca2+]ER and Arest. In addition, lowering RYR2 expression increased the threshold [Ca2+]ER and a product of Arest, and the relative expression level for each mutant correlated with threshold [Ca2+]ER, suggesting that the threshold [Ca2+]ER depends on the net Ca2+ release rate via RYR2. Modeling reproduced Ca2+ oscillations with [Ca2+]cyt and [Ca2+]ER changes in WT and CPVT cells. Interestingly, the [Ca2+]cyt-dependent activity of specific mutations correlated with the age of disease onset in patients carrying them. Our data suggest that the reduction in threshold [Ca2+]ER for spontaneous Ca2+ release by CPVT mutation is explained by enhanced [Ca2+]cyt-dependent activity without requiring modulation of the [Ca2+]ER sensitivity of RYR2.<\/jats:p>","DOI":"10.1085\/jgp.202112869","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T02:21:23Z","timestamp":1649125283000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Cytosolic Ca2+-dependent Ca2+ release activity primarily determines the ER Ca2+ level in cells expressing the CPVT-linked mutant RYR2"],"prefix":"10.1085","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5005-9698","authenticated-orcid":true,"given":"Nagomi","family":"Kurebayashi","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3845-2980","authenticated-orcid":true,"given":"Takashi","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6505-1130","authenticated-orcid":true,"given":"Ryosaku","family":"Ota","sequence":"additional","affiliation":[{"name":"Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junji","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of California San Francisco, San Francisco, CA 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazunori","family":"Kanemaru","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Medicine, Tokyo, Japan 4"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan 5"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9029-2339","authenticated-orcid":true,"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan 6"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masamitsu","family":"Iino","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Medicine, Tokyo, Japan 4"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3503-8696","authenticated-orcid":true,"given":"Fumiyoshi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-6574","authenticated-orcid":true,"given":"Takashi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan 1"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"2023072122342277000_bib1","volume-title":"Molecular Biology of the Cell","author":"Alberts","year":"1983","edition":"Sixth edition"},{"key":"2023072122342277000_bib2","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1007\/s00380-014-0555-y","article-title":"A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: A case of adult-onset catecholaminergic polymorphic ventricular tachycardia","volume":"30","author":"Arakawa","year":"2015","journal-title":"Heart Ves."},{"key":"2023072122342277000_bib3","doi-asserted-by":"publisher","first-page":"C1313","DOI":"10.1152\/ajpcell.1995.268.5.C1313","article-title":"Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes","volume":"268","author":"Bassani","year":"1995","journal-title":"Am. 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