Neuronal α2δ proteins and brain disorders

Abstract

α 2 δ proteins are membrane-anchored extracellular glycoproteins which are abundantly expressed in the brain and the peripheral nervous system. 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 2 δ 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. Recently, the human genes (CACNA2D1-4) encoding for the four known α 2 δ proteins (isoforms α 2 δ-1 to α 2 δ-4) have been linked to a large variety of neurological and neuropsychiatric disorders including epilepsy, autism spectrum disorders, bipolar disorders, schizophrenia, and depressive disorders. Here, we provide an overview of the hitherto identified disease associations of all known α 2 δ genes, hypothesize on the pathophysiological mechanisms considering their known physiological roles, and discuss the most immanent future research questions. Elucidating their specific physiological and pathophysiological mechanisms may open the way for developing entirely novel therapeutic paradigms for treating brain disorders.

Presynaptic α 2 δ subunits are key organizers of glutamatergic synapses

“…This affects our current view on excitatory synapse formation and implicates α 2 δ subunits and therefore presynaptic calcium channel complexes as potential nucleation points for the organization of synapses. Finally, these findings may provide a basis for understanding the role of α 2 δ subunits in the development and clinical manifestation of neuropsychiatric disorders ( 52 , 53 ).…”

Role of High Voltage-Gated Ca2+ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function

“…α 2 δ-1 deletion did not reduce the whole-cell Ca 2+ influx in SF1 + neurons but led to a membrane hyperpolarization and dramatically reduced electrical activity and synaptic transmission [211]. In fact, several recent studies demonstrate the role of α 2 δ proteins in synapse formation and function or neuronal excitability independent of its role as an HVCC subunit [202,212,213] but due to its interactions with NMDA [214] and GABAA receptors [215], thrombospondins [216] or BK potassium channels [217]. In pancreatic β-cells, it has been shown that the interaction of α 2 δ-1 with RalA GTPase is important for binding α 2 δ-1 on insulin granules and tethering these granules to the HVCCs in the plasma membrane [218].…”

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

“…Excellent reviews have recently been published on this topic ( Zamponi et al, 2015 ; Catterall et al, 2020 ; Dolphin and Lee, 2020 ; Ablinger et al, 2020 ) and valuable detailed information on the physiology, tissue distribution and pharmacology of these channels can be found in the NC-IUPHAR Guide to Pharmacology 1 ( Alexander et al, 2019 ).…”

“…Differences in their biophysical properties, tissue expression, subcellular targeting, association with other interacting proteins in signalosomes and in their modulation by other signaling pathways generates the functional diversity required for the many physiological functions they support ( Zamponi et al, 2015 ; Nanou and Catterall, 2018 ; Liu et al, 2020 ). Extensive alternative splicing and association with various modulatory accessory subunits (β1-β4, α2δ1-α2δ4), posttranslational modifications and RNA-editing ( Huang et al, 2012 ; Zamponi et al, 2015 ; Li et al, 2017 ; Loh et al, 2020 ) further fine-tunes their biophysical and pharmacological properties ( Buraei and Yang, 2010 ; Zamponi et al, 2015 ; Ablinger et al, 2020 ). This requirement for tight functional control explains why even minor changes in the activity of these channels induced by genetic variants can cause human disease.…”

“…For proper function and subcellular targeting Cav1 and Cav2 channels require association with one of four different β- and one of four different α2δ-subunits ( Figure 1A ; Buraei and Yang, 2010 ; Zamponi et al, 2015 ; Ablinger et al, 2020 ). Therefore, genetic variants in any of these accessory subunits can indirectly affect channel function.…”