MSTPublications: September 2022
Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2.
Wleklinski MJ, Kryshtal DO, Kim K, Parikh SS, Blackwell DJ, Marty I, Iyer VR, Knollmann BC.
Circ Res. 2022 Sep 14:101161CIRCRESAHA121320661. doi: 10.1161/CIRCRESAHA.121.320661. Online ahead of print.
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac arrhythmia syndrome triggered by catecholamines released during exercise, stress, or sudden emotion. Variants in the calsequestrin-2 gene (CASQ2), encoding the major calcium (Ca) binding protein in the sarcoplasmic reticulum (SR), are the second most common cause of CPVT. Recently, several CASQ2 gene variants, such as CASQ2-K180R, have been linked to an autosomal dominant form of Casq2-linked CPVT (CPVT2), but the underlying mechanism is not known.
Methods: A K180R mouse model was generated using CRIPSR/Cas9. Heterozygous and homozygous K180R mice were studied using telemetry ECG recordings in vivo. Ventricular cardiomyocytes were isolated and studied using fluorescent Ca indicators and patch clamp. Expression levels and localization of SR Ca-handling proteins were evaluated using Western blotting and immunostaining. Intra-SR Ca kinetics were quantified using low-affinity Ca indicators.
Results: K180R mice exhibit an autosomal dominant CPVT phenotype following exercise or catecholamine stress. Upon catecholamine stress, K180R ventricular cardiomyocytes exhibit increased spontaneous SR Ca release events, triggering delayed afterdepolarizations and spontaneous beats. K180R had no effect on levels of Casq2, Casq2 polymers, or other SR Ca-handling proteins. Intra-SR Ca measurements revealed that K180R impaired dynamic intra-SR Ca buffering, resulting in a more rapid rise of free Ca in the SR during diastole. Steady-state SR Ca buffering and total SR Ca content were not changed. Consistent with the reduced dynamic intra-SR buffering, K180R causes reduced SR Ca release refractoriness.
Conclusions: CASQ2-K180R causes CPVT2 via a heretofore unknown mechanism that differs from CASQ2 variants associated with autosomal recessive CPVT2. Unlike autosomal recessive CASQ2 variants, K180R impairs the dynamic buffering of Ca within the SR without affecting total SR Ca content or Casq2 protein levels. Our data provide insight into the molecular mechanism underlying autosomal dominant CPVT2.
An ensemble recruited by α2a-adrenergic receptors is engaged in a stressor-specific manner in mice.
Brown JA, Petersen N, Centanni SW, Jin AY, Yoon HJ, Cajigas SA, Bedenbaugh MN, Luchsinger JR, Patel S, Calipari ES, Simerly RB, Winder DG.
Neuropsychopharmacology. 2022 Sep 9. doi: 10.1038/s41386-022-01442-x. Online ahead of print.
Improving ascertainment of suicidal ideation and suicide attempt with natural language processing.
Bejan CA, Ripperger M, Wilimitis D, Ahmed R, Kang J, Robinson K, Morley TJ, Ruderfer DM, Walsh CG.
Sci Rep. 2022 Sep 7;12(1):15146. doi: 10.1038/s41598-022-19358-3.
Zooming into the COVID Era Together.
Bird EC, Pettepher CC, Ball MAZ, Goswami P, Lyons E, Reed SC, Splittgerber R, Osheroff N.
Med Sci Educ. 2022 Sep 15:1-6. doi: 10.1007/s40670-022-01611-z. Online ahead of print.