More than a pore: How voltage-gated calcium channels act on different levels of neuronal communication regulation.

Voltage-gated calcium channels (VGCCs) represent key regulators of the calcium influx through the plasma membrane of excitable cells, like neurons. Activated by the depolarization of the membrane, the opening of VGCCs induces very transient and local changes in the intracellular calcium concentration, known as calcium nanodomains, that in turn trigger calcium-dependent signaling cascades and the release of chemical neurotransmitters. Based on their central importance as concierges of excitation-secretion coupling and therefore neuronal communication, VGCCs have been studied in multiple aspects of neuronal function and malfunction. However, studies on molecular interaction partners and recent progress in omics technologies have extended the actual concept of these molecules. With this review, we want to illustrate some new perspectives of VGCCs reaching beyond their function as calcium-permeable pores in the plasma membrane. Therefore, we will discuss the relevance of VGCCs as voltage sensors in functional complexes with ryanodine receptors, channel-independent actions of auxiliary VGCC subunits, and provide an insight into how VGCCs even directly participate in gene regulation. Furthermore, we will illustrate how structural changes in the intracellular C-terminus of VGCCs generated by alternative splicing events might not only affect the biophysical channel characteristics but rather determine their molecular environment and downstream signaling pathways.