title: Allosteric modulation of [(3)H]gabapentin binding by ruthenium red.
abstract: Gabapentin is an anticonvulsant with an unknown mechanism of action. However, it has been proposed that gabapentin acts by binding to voltage-gated calcium channels. To further characterize the interaction of gabapentin with its endogenous binding site in cerebral cortex, we tested for competitive and allosteric interactions between [(3)H]gabapentin and a variety of calcium channel binding ligands. Most ligands for voltage- or ligand-gated calcium channels (verapamil, the omega-conotoxins MVIIC and GVIA, ryanodine, caffeine, capsaicin, MK-801) had no significant effect on [(3)H]gabapentin binding. However, ruthenium red, a relatively nonselective calcium channel ligand, was found to robustly modulate [(3)H]gabapentin binding. Ruthenium red slowed the association and dissociation kinetics of [(3)H]gabapentin while increasing the number of detectable binding sites. Spermine and MgCl(2), which also bind to calcium channels and modulate [(3)H]gabapentin binding, were found to act in a similar manner. These findings support the contention that the principal endogenous binding site for gabapentin is a calcium channel; they characterize the nature of the allosteric interaction of spermine, MgCl(2) and ruthenium red with this binding site; and they suggest possible mechanisms by which gabapentin may modulate calcium channel function and ultimately produce therapeutic actions.
authors.affiliation: Roche Bioscience, Neurobiology Unit, Center for Biological Research, 3401 Hillview Avenue, Palo Alto, CA 94304, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Taylor
authors.forename: D W
authors.initials: DW
authors.lastname: Bonhaus
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D066298:In Vitro Techniques; D008024:Ligands; D015636:Magnesium Chloride / Q000494:pharmacology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D012430:Ruthenium Red / Q000494:pharmacology*; D013096:Spermine / Q000494:pharmacology; D013696:Temperature; D005680:gamma-Aminobutyric Acid
chemical_list: D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D008024:Ligands; D015636:Magnesium Chloride; D012430:Ruthenium Red; D013096:Spermine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin