Non-ionotropic voltage-gated calcium channel signaling.

Voltage-gated calcium channels (VGCCs) are the major conduits for calcium ions (Ca) within excitable cells. Recent studies have highlighted the non-ionotropic functionality of VGCCs, revealing their capacity to activate intracellular pathways independently of ion flow. This non-ionotropic signaling mode plays a pivotal role in excitation-coupling processes, including gene transcription through excitation-transcription (ET), synaptic transmission via excitation-secretion (ES), and cardiac contraction through excitation-contraction (EC). However, it is noteworthy that these excitation-coupling processes require extracellular calcium (Ca) and Ca occupancy of the channel ion pore. Analogous to the "non-canonical" characterization of the non-ionotropic signaling exhibited by the N-methyl-D-aspartate receptor (NMDA), which requires extracellular Ca without the influx of ions, VGCC activation requires depolarization-triggered conformational change(s) concomitant with Ca binding to the open channel. Here, we discuss the contributions of VGCCs to ES, ET, and EC coupling as Ca binding macromolecules that transduces external stimuli to intracellular input prior to elevating intracellular Ca. We emphasize the recognition of calcium ion occupancy within the open ion-pore and its contribution to the excitation coupling processes that precede the influx of calcium. The non-ionotropic activation of VGCCs, triggered by the upstroke of an action potential, provides a conceptual framework to elucidate the mechanistic aspects underlying the microseconds nature of synaptic transmission, cardiac contractility, and the rapid induction of first-wave genes.