Non-ionotropic voltage-gated calcium channel signaling

ABSTRACT

Voltage-gated calcium channels (VGCCs) are the major conduits for calcium ions (Ca²⁺) 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 (Ca²⁺) and Ca²⁺ 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 Ca²⁺ without the influx of ions, VGCC activation requires depolarization-triggered conformational change(s) concomitant with Ca²⁺ binding to the open channel. Here, we discuss the contributions of VGCCs to ES, ET, and EC coupling as Ca²⁺ binding macromolecules that transduces external stimuli to intracellular input prior to elevating intracellular Ca²⁺. 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.

KEYWORDS:

• Excitation transcription (ET) coupling
• CICR
• cardiac excitation contraction (EC) coupling
• synaptic transmission
• L-type Ca²⁺ channel
• conformational coupling

Acknowledgments

The authors apologize that not all primary papers could not be cited in some cases, owing to a limit on the number of references.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contribution

D.A, Conceptualization, Data analysis, Methodology, Writing – original draft; M.T, Data acquisition and analysis, Methodology, review and editing

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.