Abstract
Voltage-gated calcium (CaV) channels are associated with β and α2δ auxiliary subunits. This review will concentrate on the function of the α2δ protein family, which has four members. The canonical role for α2δ subunits is to convey a variety of properties on the CaV1 and CaV2 channels, increasing the density of these channels in the plasma membrane and also enhancing their function. More recently, a diverse spectrum of non-canonical interactions for α2δ proteins has been proposed, some of which involve competition with calcium channels for α2δ or increase α2δ trafficking and others which mediate roles completely unrelated to their calcium channel function. The novel roles for α2δ proteins which will be discussed here include association with low-density lipoprotein receptor-related protein 1 (LRP1), thrombospondins, α-neurexins, prion proteins, large conductance (big) potassium (BK) channels, and N-methyl-d-aspartate (NMDA) receptors.
Highlights
Voltage-gated calcium (Ca ) channels are ubiquitously presentV in excitable cells and are essential for their function
Α2δ, conveys a variety of properties on the channels but recently has been reported to have distinct effects on both other ion channels and other biological processes. These novel aspects of α2δ function are the subject of this review. This topic is important, as α2δ-1 is the therapeutic target of the α2δ ligand class of drugs[3,4], which are widely prescribed for several indications, including many types of neuropathic pain
We found that longer-term incubation of cultured cells with gabapentin produced a clear reduction of calcium currents, both in Trafficking of α2δ-1 by the multifunctional transport protein lipoprotein receptor-related protein 1 (LRP1) The low-density lipoprotein receptor-related protein (LRP) family represents a large group of ligand-binding and trafficking proteins, including the low-density lipoprotein (LDL) receptor and LRP1–6
Summary
V in excitable cells and are essential for their function. They can be divided into three classes (Ca 1–3). In several studies, the binding partners have been found to sequester α2δ proteins, limiting their access to the CaV channels, reducing both the function and the plasma membrane localization of calcium channels This mechanism has been proposed for α-neurexins[11] and for BK channels[13] as well as pathologically for a mutant form of prion protein (PrP)[84]. New roles independent of calcium channels have been proposed for specific α2δ proteins (for example, interaction with TSPs14 and as a subunit of NMDA receptors[15]). One possible reason is that it might be indirect (for example, via a scaffolding protein expressed in the spinal cord, interacting with both α2δ-1 and NMDA receptors)
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