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.

Endogenous ß-neurexins on axons and within synapses show regulated dynamic behavior.

Neurexins are key organizer molecules that regulate synaptic function and are implicated in autism and schizophrenia. ß-neurexins interact with numerous cell adhesion and receptor molecules, but their neuronal localization remains elusive. Using single-molecule tracking and high-resolution microscopy to detect neurexin1ß and neurexin3ß in primary hippocampal neurons from knockin mice, we demonstrate that endogenous ß-neurexins are present in fewer than half of excitatory and inhibitory synapses. Moreover, we observe a large extrasynaptic pool of ß-neurexins on axons and show that axonal ß-neurexins diffuse with higher surface mobility than those transiently confined within synapses. Stimulation of neuronal activity further increases the mobility of synaptic and axonal ß-neurexins, whereas inhibition causes the opposite. Blocking ectodomain cleavage by metalloproteases also reduces ß-neurexin mobility and enhances glutamate release. These findings suggest that the surface mobility of endogenous ß-neurexins inside and outside of synapses is dynamically regulated and linked to neuronal activity.