The R-Domain: Identification of an N-terminal Region of the α₂δ-1 Subunit Which is Necessary and Sufficient for its Effects on Ca_v2.2 Calcium Currents

Title:The R-Domain: Identification of an N-terminal Region of the α₂δ-1 Subunit Which is Necessary and Sufficient for its Effects on Ca_v2.2 Calcium Currents

Volume: 8

Author(s): Lele Song, Italo A. Espinoza-Fuenzalida, Sarah Etheridge, Owen T. Jones and Elizabeth M. Fitzgerald

Affiliation:

Keywords: Calcium influx, gabapentinoids, gene expression, muscle contraction, neurotransmission, voltage-gated calcium channels.

Abstract: Voltage-gated calcium channels (Ca_v) and their associated proteins are pivotal signalling complexes in excitable cell physiology. In nerves and muscle, Ca_v tailor calcium influx to processes including neurotransmission, muscle contraction and gene expression. Ca_v comprise a pore-forming α1 and modulatory β and α₂δ subunits – the latter targeted by anti-epileptic and anti-nociceptive gabapentinoid drugs. However, the mechanisms of gabapentinoid action are unclear, not least because detailed structure-function mapping of the α₂δ subunit remains lacking. Using molecular biology and electrophysiological approaches we have conducted the first systematic mapping of α₂δ subunit structurefunction. We generated a series of cDNA constructs encoding chimera, from which successive amino acids from the rat α₂δ-1 subunit were incorporated into a Type 1 reporter protein – PIN-G, to produce sequential extensions from the transmembrane (TM) region towards the N-terminus. By successive insertion of a TGA stop codon, a further series of N- to Cterminal extension constructs lacking the TM region, were also generated. Using this approach we have defined the minimal region of α₂δ-1 - we term the R-domain (Rd), that appears to contain all the machinery necessary to support the electrophysiological and trafficking effects of α₂δ-1 on Ca_v. Structural algorithms predict that Rd is conserved across all four α₂δ subunits, including RNA splice variants, and irrespective of phyla and taxa. We suggest, therefore, that Rd likely constitutes the major locus for physical interaction with the α₁ subunit and may provide a target for novel Ca_v therapeutics.

Cite this article as:

Song Lele, Espinoza-Fuenzalida A. Italo, Etheridge Sarah, Jones T. Owen and Fitzgerald M. Elizabeth, The R-Domain: Identification of an N-terminal Region of the α₂δ-1 Subunit Which is Necessary and Sufficient for its Effects on Ca_v2.2 Calcium Currents, Current Molecular Pharmacology 2015; 8 (2) . https://dx.doi.org/10.2174/1874467208666150507104555