Voltage-gated calcium channels function as Ca2+-activated signaling receptors

•The Ca2+-bound voltage-gated channel operates as a Ca2+ binding receptor.•A Ca2+-bound channel triggers synchronous release prior to Ca2+ influx.•A conformational change is conveyed from the channel to syntaxin 1A via intramembrane signaling.•A Ca2+-bound channel drives cardiac contraction in neonate cardiomyocytes independent of Ca2+ influx. Voltage-gated calcium channels (VGCCs) are transmembrane cell surface proteins responsible for multifunctional signals. In response to voltage, VGCCs trigger synaptic transmission, drive muscle contraction, and regulate gene expression. Voltage perturbations open VGCCs enabling Ca2+ binding to the low affinity Ca2+ binding site of the channel pore. Subsequent to permeation, Ca2+ targets selective proteins to activate diverse signaling pathways. It is becoming apparent that the Ca2+-bound channel triggers secretion in excitable cells and drives contraction in cardiomyocytes prior to Ca2+ permeation. Here, I highlight recent data implicating receptor-like function of the Ca2+-bound channel in converting external Ca2+ into an intracellular signal. The two sequential mechanistic perspectives of VGCC function are discussed in the context of the prevailing and long-standing current models of depolarization-evoked secretion and cardiac contraction.