Emerging roles for α2δ subunits in calcium channel function and synaptic connectivity
Introduction
Voltage-gated calcium channels (VGCCs) are essential for the function of excitable cells by permitting Ca2+ entry in response to membrane depolarization. Depending on their physiological profiles, VGCCs are categorized into multiple types including those that open at high voltages and possess larger conductances (L-types, N-types, P/Q-types and R-types) or those associated with low voltages and rapid inactivation (T-type) [1]. In terms of structure, the high-voltage-activated (HVA) channels are comprises the main pore-forming subunit, α1, along with the auxiliary subunits, β and α2δ, with an additional γ subunit found primarily in skeletal muscle. Though not directly involved in Ca2+ transport, the β and α2δ are critical for VGCC function by regulating kinetics and cell surface expression of these channels [2]. The α2δ subunit is encoded by four genes (Cacna2d1-4), resulting in four isoforms (α2δ-1-4) that each consist of disulfide-linked α2 and δ peptides. All four isoforms are expressed throughout the central nervous system (CNS), where their localization and properties have been extensively reviewed elsewhere [3, 4, 5]. For this review, we will focus on recent findings with regard to the roles of α2δ in Ca2+ channel trafficking and function in nervous tissue as well as in modulating synapse formation and transmission. We will end with a brief discussion regarding the implications of α2δ dysfunction in disorders of the CNS.
Section snippets
α2δ in calcium channel localization and function
α2δ subunits are important for trafficking VGCC α1 subunits to the plasma membrane (Figure 1), a key step in regulating calcium conduction at the neuronal surface [4]. There are four α2δ isoforms encoded by four distinct genes (Cacna2d1, Cacna2d2, Cacna2d3, and Cacna2d4), each encoding a single polypeptide that is later cleaved into α2 and δ fragments post-translationally [6]. In a well-known sensory circuit in spinal cord, α2δ-1 directs Cav2.2 (an N-type VGCC) to the surface of dorsal root
α2δ and the formation and function of synaptic connectivity
Though long known for regulating calcium channel expression in synaptic membranes, α2δ subunits have only recently been identified as important regulators of synaptic connectivity in the nervous system, particularly by serving as receptors for secreted proteins. Astrocytes, the most abundant glial cell in the brain, are essential participants in developmental synapse formation via the secretion of factors that either promote or inhibit this process [19, 20, 21]. The first of these
Roles of α2δ in injury, disease, and addiction
As the importance of α2δ has become increasingly apparent for normal synaptic and network function, the implications of dysfunctional α2δ signaling in disorders of the nervous system continue to expand (see Table 1 for summary). Many of the investigations into α2δ and disease up to this point have involved the conditions of chronic or neuropathic pain, with a recent review article [47] highlighting the importance of the α2δ-1 subunit in the pathology and treatment of pain. New evidence
Conclusion
In summary, the known functions of the α2δ family in the nervous system are continuing to expand. From increased insight into surface trafficking and gating of VGCCs to novel mechanisms of circuit-specific synapse formation and function, we have now moved well beyond their humble origins as auxiliary channel subunits and are acknowledging them as powerful regulators of crucial developmental and disease-specific processes.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
WCR is supported by the John and Polly Sparks Foundation and the Brain & Behavior Research FoundationNARSAD Young Investigator Award 27662. The relevant work in the Eroglu laboratory is supported by N.I.H.R01-NS096352 to CE.
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