Preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) resulted in near-complete attenuation of the beta-adrenergic contractile response and diminished exercise capacity.
Does expression of mutant calcium-channel β-subunits improve cardiac contractility in Rad-phosphosite-mutant mice?
Disruption of the interaction between Rad and calcium channels rescues failing heart phenotypes in mice, identifying a novel mechanistic target for enhancing cardiac contractility.
Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for β-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of β-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel β-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.
Papa et al. (Mon,) conducted a other in Cardiac contractility and fight-or-flight response. 4SA-Rad mutation (preventing Rad phosphorylation) vs. Wild-type (WT) was evaluated on Isoproterenol-induced augmentation of Ca2+ current and contractility. Preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) resulted in near-complete attenuation of the beta-adrenergic contractile response and diminished exercise capacity.