The heteromultimeric voltage-sensitive calcium (Ca²⁺) channel is involved in the function of excitable tissues including sensory nerves. It comprises a primary α1 subunit and auxiliary α2δ, β and γ subunits, and the associated α2δ ligand-binding site (see fig 1). The α1 subunit forms the ion-conducting pore and serves as voltage sensor. The α2δ subunit consists of the highly N-glycosylated extracellular α2 protein attached to the membrane-spanning δ protein that binds divalent metal cations and interacts directly with the α1 subunit. The β subunit is an intracellular protein that mediates modulation of Ca²⁺ channel function by intracellular kinases. The γ subunit is a glycoprotein with four transmembrane segments.¹

Pregabalin is a second-generation α2δ ligand that is approved in Europe for the treatment of neuropathic pain and epilepsy, and in the US for the management of neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia and as an adjunctive treatment for adults with partial onset seizures. It is 2–10 times more potent and has more predictable pharmacological effects than the prototype α2δ ligand, gabapentin. Although it is structurally related to γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, it is functionally unrelated and inactive at GABA_A, GABA_B or benzodiazapine receptors and is not converted metabolically into GABA or a GABA agonist. Furthermore, clinically effective concentrations of pregabalin have been shown to have no effect on GABA uptake or degradation.^2,3

Pregabalin binds potently to the α2δ auxiliary protein associated with voltage-gated calcium channels, …