1) but considerably different in α 2δ-3 and α 2δ-4 (Fig. The genes contain 38 or 39 exons, and the distribution of exons over the gene is similar between α 2δ-1 and α 2δ-2 (Fig.
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In the human genome, four genes (CACNA2D1–4) code for four α 2δ proteins (α 2δ-1 to α 2δ-4), which give rise to multiple transcripts as the result of alternative splicing. Furthermore, we discuss channel-dependent and channel-independent mechanisms of potential relevance for the respective pathophysiological mechanisms. In this review, we provide an overview of the known and putative associations of α 2δ genes and proteins with human neurological disorders. α 2δ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin and have been linked to a large variety of diseases. An increasing number of studies, however, suggest functions independent of the calcium channel complex. Α 2δ proteins are membrane-anchored extracellular glycoproteins which have initially been identified as subunits of voltage-gated calcium channels (VGCCs). Elucidating their specific physiological and pathophysiological mechanisms may open the way for developing entirely novel therapeutic paradigms for treating brain disorders. Here, we provide an overview of the hitherto identified disease associations of all known α 2δ genes, hypothesize on the pathophysiological mechanisms considering their known physiological roles, and discuss the most immanent future research questions. Recently, the human genes (CACNA2D1–4) encoding for the four known α 2δ proteins (isoforms α 2δ-1 to α 2δ-4) have been linked to a large variety of neurological and neuropsychiatric disorders including epilepsy, autism spectrum disorders, bipolar disorders, schizophrenia, and depressive disorders. α 2δ proteins are the targets of the widely prescribed anti-epileptic and anti-allodynic drugs gabapentin and pregabalin, particularly for the treatment of neuropathic pain conditions. They serve as regulatory subunits of voltage-gated calcium channels and, particularly in nerve cells, regulate presynaptic and postsynaptic functions independently from their role as channel subunits. Α 2δ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system.
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