Ca²⁺-dependent regulation of cardiac L-type Ca²⁺ channels: Is a unifying mechanism at hand?

Ca²⁺ entry (I_Ca) through cardiac L-type Ca²⁺ channels (LTCC) drives critical cellular processes ranging from contraction to gene expression, and, when disordered, is implicated in arrhythmias and hypertrophy. LTCC activation occurs by cell membrane depolarization, but LTCCs are also regulated by auxiliary proteins, phosphorylation, and intracellular CA²⁺ ([Ca²⁺]_i). LTCC regulation by [Ca²⁺]_i is especially intriguing because increased [Ca²⁺]_i signals dual and conflicting commands for I_Ca inactivation and facilitation. A recent explosion of work has shed new light on the mechanisms and molecular identity of domains necessary for [Ca²⁺]_i-dependent regulation of LTCC.