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α2δ ligand: a new, smart pill for visceral pain in patients with hypersensitive irritable bowel syndrome?
  1. Michael Camilleri
  1. Correspondence to:
    Dr Michael Camilleri
    Mayo Clinic, Charlton 8-110, 200 First St SW, Rochester, MN 55905, USA; camilleri.michael{at}mayo.edu

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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

Figure 1

 Three dimensional reconstruction of the L-type calcium channel showing α2δ ligand-binding site. This figure was published in Trends in Pharmacological Sciences, volume 28; Dooley, Taylor, Donevan et al; Ca2+ channel α2δ ligands: novel modulators of neurotransmission, 75–82; copyright Elsevier, 2007.8

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 GABAA, GABAB 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, …

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