Pharmacological disruption of calcium channel trafficking by the α 2 δ ligand gabapentin
- 4 March 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (9), 3628-3633
- https://doi.org/10.1073/pnas.0708930105
Abstract
The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the α2δ-1 and α2δ-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of α2δ subunits to enhance voltage-gated Ca2+channel plasma membrane density by means of an effect on trafficking. Our results conclusively demonstrate that GBP inhibits calcium currents, mimicking a lack of α2δ only when applied chronically, but not acutely, both in heterologous expression systems and in dorsal root-ganglion neurons. GBP acts primarily at an intracellular location, requiring uptake, because the effect of chronically applied GBP is blocked by an inhibitor of the system-L neutral amino acid transporters and enhanced by coexpression of a transporter. However, it is mediated by α2δ subunits, being prevented by mutations in either α2δ-1 or α2δ-2 that abolish GBP binding, and is not observed for α2δ-3, which does not bind GBP. Furthermore, the trafficking of α2δ-2 and CaV2 channels is disrupted both by GBP and by the mutation in α2δ-2, which prevents GBP binding, and we find that GBP reduces cell-surface expression of α2δ-2 and CaV2.1 subunits. Our evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of α2δ subunit function, thereby impairing the trafficking function of the α2δ subunits to which it binds.Keywords
This publication has 41 references indexed in Scilit:
- Functional biology of the α2δ subunits of voltage-gated calcium channelsTrends in Pharmacological Sciences, 2007
- Identification of the α 2 -δ-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalinProceedings of the National Academy of Sciences of the United States of America, 2006
- Calcium channel α2δ1 subunit mediates spinal hyperexcitability in pain modulationPain, 2006
- Pregabalin Reduces the Release of Synaptic Vesicles from Cultured Hippocampal NeuronsPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2006
- Mediation of Highly Concentrative Uptake of Pregabalin by L-Type Amino Acid Transport in Chinese Hamster Ovary and Caco-2 CellsThe Journal of pharmacology and experimental therapeutics, 2005
- Gabapentin fails to alter P/Q‐type Ca2+ channel‐mediated synaptic transmission in the hippocampus in vitroSynapse, 2005
- PI3K promotes voltage-dependent calcium channel trafficking to the plasma membraneNature Neuroscience, 2004
- Importance of the Different |β Subunits in the Membrane Expression of the α1A and α2 Calcium Channel Subunits: Studies Using a Depolarization‐sensitive α1A AntibodyEuropean Journal of Neuroscience, 1997
- Properties of Cloned Rat α1A Calcium Channels Transiently Expressed in the COS‐7 Cell LineEuropean Journal of Neuroscience, 1997
- The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the α2δ Subunit of a Calcium ChannelJournal of Biological Chemistry, 1996