The L-type calcium channel current modulation mechanism: the plot thickens and fogs

The acute stress response, colloquially referred to as the fight-or-flight response, initiates with a burst of sympathetic nervous system (SNS) activity resulting in elevated catecholaminergic signaling. -adrenergic receptors (-ARs) on cardiomyocytes transmit SNS activity into elevated cardiac output. The L-type calcium channel complex (LTCC) is an initial proximal effector of -AR activation in the myocardium. Catecholaminergic activation of -ARs results in increased Ca 2+ current through the LTCC (I Ca,L ) with channel activation occurring at lower membrane voltage. The net effect is increased I Ca,L , resulting in accentuated excitation-contraction coupling in the ventricle and faster spontaneous depolarization in the sinoatrial node, thus contributing to increased contraction and faster heart rate, respectively. This increased I Ca,L by -AR signaling is commonly called modulation. Despite the central physiological importance of Ca V 1.2 modulation combined with extensive investigations to uncover molecular mechanisms of action, we still don't know how the LTCC is modulated.