LAUSR

It has been clear for over 100 years that Ca 2+ and catecholamines perform central roles necessary for sustaining and modulating heart function. However, despite years of study, the cellular and molecular mechanisms underpinning adrenergic receptor agonist activation of voltage-gated Ca2+ current have been far less certain. The voltage-gated Ca2+ channel CaV1.2 is the primary pathway for extracellular Ca2+ to enter myocardium. This process is by necessity tightly controlled, in part, because of the steep extracellular—intracellular gradient, where extracellular Ca2+ concentration is 10 000×greater than resting intracellular Ca2+ concentration. To avoid pathological intracellular Ca2+ overload, the CaV1.2 current (ICa) is meted out in discrete pulses, substantially under the control of cell membrane voltage and adrenergic tone, to direct excitation-contraction coupling and inotropy, and to influence metabolism and gene transcription. Unfortunately, in tough times, loss of normal Ca2+ homeostasis contributes to myocardial dysfunction, arrhythmias, and death. Thus, understanding the control points for operating this system is an important goal for cardiovascular research. Work published in this issue of Circulation Research by Papa et al1 provides new genetic insights into a mechanism for how CaV1.2 operates with a higher probability of opening in heart failure,2 a circumstance contributing to arrhythmia and, perhaps, to heart failure itself.