title: Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury.
abstract: The α2δ-1 protein is an auxiliary subunit of voltage-gated calcium channels, critical for neurotransmitter release. It is upregulated in dorsal root ganglion (DRG) neurons following sensory nerve injury, and is also the therapeutic target of the gabapentinoid drugs, which are efficacious in both experimental and human neuropathic pain conditions. α2δ-1 has 3 spliced regions: A, B, and C. A and C are cassette exons, whereas B is introduced via an alternative 3' splice acceptor site. Here we have examined the presence of α2δ-1 splice variants in DRG neurons, and have found that although the main α2δ-1 splice variant in DRG is the same as that in brain (α2δ-1 ΔA+B+C), there is also another α2δ-1 splice variant (ΔA+BΔC), which is expressed in DRG neurons and is differentially upregulated compared to the main DRG splice variant α2δ-1 ΔA+B+C following spinal nerve ligation. Furthermore, this differential upregulation occurs preferentially in a small nonmyelinated DRG neuron fraction, obtained by density gradient separation. The α2δ-1 ΔA+BΔC splice variant supports CaV2 calcium currents with unaltered properties compared to α2δ-1 ΔA+B+C, but shows a significantly reduced affinity for gabapentin. This variant could therefore play a role in determining the efficacy of gabapentin in neuropathic pain.
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
authors: Beatrice
authors: B
authors: Lana
authors: Bettina
authors: B
authors: Schlick
authors: Stuart
authors: S
authors: Martin
authors: Wendy S
authors: WS
authors: Pratt
authors: Karen M
authors: KM
authors: Page
authors: Leonor
authors: L
authors: Goncalves
authors: Wahida
authors: W
authors: Rahman
authors: Anthony H
authors: AH
authors: Dickenson
authors: Claudia S
authors: CS
authors: Bauer
authors: Annette C
authors: AC
authors: Dolphin
mesh_terms: D000588:Amines / Q000378:metabolism*; D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism*; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000378:metabolism*; D008297:Male; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000588:Amines; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D020033:Protein Isoforms; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin
keywords: Alpha2delta (α(2)δ); Calcium channel; Gabapentin; Neuropathic pain; Splice variant