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The RyR2-P2328S mutation produces catecholaminergic polymorphic ventricular tachycardia (CPVT) and AF in hearts from homozygous RyR2P2328S\/P2328S (denoted RyR2S\/S) mice. We have now examined P2328S RyR2 channels from RyR2S\/S hearts. The activity of wild-type (WT) and P2328S RyR2 channels was similar at a cytoplasmic [Ca2+] of 1\u2005mM, but P2328S RyR2 was significantly more active than WT at a cytoplasmic [Ca2+] of 1\u2005\u00b5M. This was associated with a &amp;gt;10-fold shift in the half maximal activation concentration (AC50) for Ca2+ activation, from \u223c3.5\u2005\u00b5M Ca2+ in WT RyR2 to \u223c320\u2005nM in P2328S channels and an unexpected &amp;gt;1000-fold shift in the half maximal inhibitory concentration (IC50) for inactivation from \u223c50\u2005mM in WT channels to \u22647\u2005\u03bcM in P2328S channels, which is into systolic [Ca2+] levels. Unexpectedly, the shift in Ca2+ activation was not associated with changes in sub-conductance activity, S2806 or S2814 phosphorylation or the level of FKBP12 (also known as FKBP1A) bound to the channels. The changes in channel activity seen with the P2328S mutation correlate with altered Ca2+ homeostasis in myocytes from RyR2S\/S mice and the CPVT and AF phenotypes.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.229039","type":"journal-article","created":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T14:31:34Z","timestamp":1556289094000},"source":"Crossref","is-referenced-by-count":21,"title":["Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse"],"prefix":"10.1242","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5793-2349","authenticated-orcid":false,"given":"Samantha C.","family":"Salvage","sequence":"first","affiliation":[{"name":"University of Cambridge 1 Physiological Laboratory , , Downing Street, Cambridge, CB2 3EG , UK"},{"name":"University of Cambridge 2 Department of Biochemistry , , Tennis Court Road, Cambridge, CB2 1QW , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther M.","family":"Gallant","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, The Australian National University 3 , 131 Garran Road, Acton ACT 2601 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8212-2209","authenticated-orcid":false,"given":"Nicole A.","family":"Beard","sequence":"additional","affiliation":[{"name":"Centre for Research in Therapeutic Solutions 4 , Faculty of Science and Technology , , Bruce, ACT 2617 , Australia"},{"name":"University of Canberra 4 , Faculty of Science and Technology , , Bruce, ACT 2617 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiraz","family":"Ahmad","sequence":"additional","affiliation":[{"name":"University of Cambridge 1 Physiological Laboratory , , Downing Street, Cambridge, CB2 3EG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haseeb","family":"Valli","sequence":"additional","affiliation":[{"name":"University of Cambridge 1 Physiological Laboratory , , Downing Street, Cambridge, CB2 3EG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-1883","authenticated-orcid":false,"given":"James A.","family":"Fraser","sequence":"additional","affiliation":[{"name":"University of Cambridge 1 Physiological Laboratory , , Downing Street, Cambridge, CB2 3EG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-6112","authenticated-orcid":false,"given":"Christopher L.-H.","family":"Huang","sequence":"additional","affiliation":[{"name":"University of Cambridge 1 Physiological Laboratory , , Downing Street, Cambridge, CB2 3EG , UK"},{"name":"University of Cambridge 2 Department of Biochemistry , , Tennis Court Road, Cambridge, CB2 1QW , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9493-4944","authenticated-orcid":false,"given":"Angela F.","family":"Dulhunty","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, The Australian National University 3 , 131 Garran Road, Acton ACT 2601 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,5,21]]},"reference":[{"key":"2024061318134294800_JCS229039C1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/0014-5793(94)01001-3","article-title":"Single channel activity of the ryanodine receptor calcium release channel is modulated by FK-506","volume":"352","author":"Ahern","year":"1994","journal-title":"FEBS Lett."},{"key":"2024061318134294800_JCS229039C2","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.amjcard.2004.10.057","article-title":"Unusual clinical presentation in a family with catecholaminergic polymorphic ventricular tachycardia due to a G14876A ryanodine receptor gene mutation","volume":"95","author":"Allouis","year":"2005","journal-title":"Am. 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