Emerging evidence for specific neuronal functions of auxiliary calcium channel α2δ subunits

Abstract

Abstract. In nerve cells the ubiquitous second messenger calcium regulates a variety of vitally important functions including neurotransmitter release, gene regulation, and neuronal plasticity. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which consist of a heteromultimeric complex of a pore forming α 1 , and the auxiliary β and α 2 δ subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached α 2 δ subunits (α 2 δ-1 to α 2 δ-4), out of which three isoforms (α 2 δ-1 to -3) are strongly expressed in the central nervous system. Over the years a wealth of studies has demonstrated the classical role of α 2 δ subunits in channel trafficking and calcium current modulation. Recent studies in specialized neuronal cell systems propose roles of α 2 δ subunits beyond the classical view and implicate α 2 δ subunits as important regulators of synapse formation. These findings are supported by the identification of novel human disease mutations associated with α 2 δ subunits and by the fact that α 2 δ subunits are the target of the anti-epileptic and anti-allodynic drugs gabapentin and pregabalin. Here we review the recently emerging evidence for specific as well as redundant neuronal roles of α 2 δ subunits and discuss the mechanisms for establishing and maintaining specificity.

NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

“…Gene set enrichment analysis (GSEA) of genes ranked by their change in H3K27ac between NRL/CRX-high and low tumors revealed a positive enrichment for rhodopsin pathway genes and a negative enrichment for genes associated with MYCN amplification (Figure 1H,I). Exemplary genes discriminating NRL/CRX-high vs. NRL/CRX-low tumors in Group 3 include CACNA2D1 , a calcium channel subunit implicated in neuronal/retinal development (Geisler et al, 2015), with evidence of overlapping NRL and CRX co-motifs and high expression levels in NRL/CRX-high tumors (Figure 1J,L). In contrast, NRL/CRX-low tumors exhibit higher levels of ERN1, a serine/threonine kinase preferentially expressed in cortical, hippocampal, and olfactory neurons (Miyoshi et al, 2000) (Figure 1K,L).…”

Regulation of Postsynaptic Stability by the L-type Calcium Channel Ca_V1.3 and its Interaction with PDZ Proteins

“…On the one hand, neurons express a number of channel isoforms displaying distinct gating and current properties. On the other hand, single channels may be functionally distinct with respect to differential targeting to specific neuronal compartments, their interactions with auxiliary calcium channel subunits, or by the formation of macro-molecular complexes with specific up- and downstream signaling proteins (for review see [1, 2]). L-type voltage-dependent calcium channels (LTCCs) occupy a key position in the activity-dependent regulation of neuronal development and thereby in mediating different forms of synaptic plasticity and in activity-induced regulation of gene expression.…”

Transcriptional regulation of voltage‐gated Ca2+ channels

“…This study provided the basis for an understanding of the regulatory mechanisms that govern the α 2 δ ‐1 subunit expression and is of relevance because α 2 δ ‐1 may play other roles unrelated to Ca V channel function. Downregulation of this protein may result in altered cell attachment and migration of skeletal myocytes and have a role in synaptogenesis in neurones . In addition, mutations in the CACNA2D1 gene are associated with cardiac dysfunction, and experimental peripheral nerve injury results in increased levels of α 2 δ ‐1 protein in sensory DRG neurones and in presynaptic terminals in the spinal cord, suggesting a role for α 2 δ ‐1 in the development of neuropathic pain …”

“…Four separate genes code for the α 2 δ subunits which display distinct tissue distribution and strong expression in the developing and mature CNS . The α 2 δ proteins consist of post‐translationally cleaved α 2 and δ peptides which remain associated with each other by a single disulphide bond, and glycosylation of α 2 δ seems to be required for the functional membrane expression of Ca V channels .…”