Cardiac Ca _V 1.2 channels require β subunits for β-adrenergic–mediated modulation but not trafficking

Ca ²⁺ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant α _1C subunits lacking capacity to bind Ca _V β can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca ²⁺ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts. Similarly, viral-mediated expression of a β-subunit–sequestering peptide sharply curtailed β-adrenergic stimulation of WT Ca ²⁺ channels, identifying an approach to specifically modulate β-adrenergic regulation of cardiac contractility. Our data demonstrate that β subunits are required for β-adrenergic regulation of Ca _V 1.2 channels and positive inotropy in the heart, but are dispensable for Ca _V 1.2 trafficking to the adult cardiomyocyte cell surface, and for basal function and excitation-contraction coupling.