title: FKBPs facilitate the termination of spontaneous Ca2+ release in wild-type RyR2 but not CPVT mutant RyR2.
abstract: FK506-binding proteins 12.6 (FKBP12.6) and 12 (FKBP12) tightly associate with the cardiac ryanodine receptor (RyR2). Studies suggest that dissociation of FKBP12.6 from mutant forms of RyR2 contributes to store overload-induced Ca(2+) release (SOICR) and Ca(2+)-triggered arrhythmias. However, these findings are controversial. Previous studies focused on the effect of FKBP12.6 on the initiation of SOICR and did not explore changes in the termination of Ca(2+) release. Less is known about FKBP12. We aimed to determine the effect of FKBP12.6 and FKBP12 on the termination of SOICR. Using single-cell imaging, in cells expressing wild-type RyR2, we found that FKBP12.6 and FKBP12 significantly increase the termination threshold of SOICR without changing the activation threshold of SOICR. This effect, dependent on the association of each FKBP with RyR2, reduced the magnitude of Ca(2+) release but had no effect on the propensity for SOICR. In contrast, neither FKBP12.6 nor FKBP12 was able to regulate an arrhythmogenic variant of RyR2, despite a conserved protein interaction. Our results suggest that both FKBP12.6 and FKBP12 play critical roles in regulating RyR2 function by facilitating the termination of SOICR. The inability of FKBPs to mediate a similar effect on the mutant RyR2 represents a novel mechanism by which mutations within RyR2 lead to arrhythmia.
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Joe Z
authors.initials: JZ
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Helen M M
authors.initials: HM
authors.lastname: Waddell
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Ella
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Jhanvi
authors.initials: J
authors.lastname: Dholakia
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Chidinma A
authors.initials: CA
authors.lastname: Okolo
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand.
authors.forename: Janet C
authors.initials: JC
authors.lastname: McLay
authors.affiliation: Department of Physiology, Otago School of Medical Sciences and Heart, University of Otago, Dunedin 9054, New Zealand pete.jones@otago.ac.nz.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Jones
mesh_terms: D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport / Q000235:genetics / Q000502:physiology; D009154:Mutation; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium
keywords: Ca2+ release; FKBPs; cardiac arrhythmias; ryanodine receptor; store overload-induced Ca2+ release