https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34969 d = 121 ± 14 nM. Ex-vivo phosphorylation/dephosphorylation experiments suggested that the divergent CaM regulation of healthy and failing human RyR2 was caused by differences in RyR2 phosphorylation by protein kinase A and Ca-CaM-dependent kinase II. Ca²⁺-spark measurements in murine cardiomyocytes harbouring RyR2 phosphomimetic or phosphoablated mutants at S2814 and S2808 suggest that phosphorylation of residues corresponding to either human RyR2-S2808 or S2814 is both necessary and sufficient for RyR2 regulation by CaM. Our results challenge the current concept that CaM universally functions as a canonical inhibitor of RyR2 across species. Rather, CaM's biological action on human RyR2 appears to be more nuanced, with inhibitory activity only on phosphorylated RyR2 channels, which occurs during exercise or in patients with heart failure.]]> Wed 24 Jun 2020 11:42:42 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7460 Sat 24 Mar 2018 08:38:50 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7968 Sat 24 Mar 2018 08:33:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9879 Sat 24 Mar 2018 08:12:48 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19035 Sat 24 Mar 2018 08:05:26 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17743 -/- myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca²⁺ waves at clinically relevant concentrations, whereas Na⁺ channel inhibitors without RyR2 blocking properties did not. In Casq2^-/- mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na⁺ channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy. RyR2 cardiac Ca²⁺ release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2^-/- mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.]]> Sat 24 Mar 2018 07:57:39 AEDT ]]>