Regulation of murine cardiac contractility by activation of α1A-adrenergic receptor-operated Ca2+ entry

Aims Sympathetic regulation of cardiac contractility is mediated in part by a1- adrenergic receptors (ARs), and the alpha(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about alpha(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediates alpha(1A)-AR-coupled cardiac contractility. Methods and results Using a transgenic model of enhanced cardiac alpha(1A)-AR expression and signalling (alpha(1A)-H mice), we identified a receptor-coupled signalling pathway that enhances Ca2+ entry and increases contractility. This pathway involves alpha(1A)-AR-activated translocation of Snapin and the transient receptor potential canonical 6 (TRPC6) channel to the plasma membrane. In ventricular cardiomyocytes from alpha(1A)-H and their non-transgenic littermates (or WTs), stimulation with alpha(1A)-AR-specific agonists resulted in increased [Ca2+](i), which was dose-related and proportional to the level of alpha(1A)-AR expression. Blockade of TRPC6 inhibited the alpha(1A)-AR-mediated increase in [Ca2+](i) and contractility. External Ca2+ entry, underlying the [Ca2+](i) increase, was not due to store-operated Ca2+ entry but to a receptor-operated mechanism of Ca2+ entry resulting from alpha(1A)-AR activation. Conclusion These findings indicate that Ca2+ entry via the alpha(1A)-AR-Snapin-TRPC6-pathway plays an important role in physiological regulation of cardiac contractility and may be an important target for augmenting cardiac performance.