Differential upregulation in DRG neurons of an α(2)δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury

The α(2)δ-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. α(2)δ-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 α(2)δ-1 splice variants in DRG neurons, and have found that although the main α(2)δ-1 splice variant in DRG is the same as that in brain (α(2)δ-1 ΔA+B+C), there is also another α(2)δ-1 splice variant (ΔA+BΔC), which is expressed in DRG neurons and is differentially upregulated compared to the main DRG splice variant α(2)δ-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 α(2)δ-1 ΔA+BΔC splice variant supports Ca(V)2 calcium currents with unaltered properties compared to α(2)δ-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.