Gabapentid is an anticonvulsant with an unknown mechanism of action. Howeve
r, it has been proposed that gabapentin acts by binding to voltage-gated ca
lcium channels. To further characterize the interaction of gabapentin with
its endogenous binding site in cerebral cortex, we tested for competitive a
nd allosteric interactions between [H-3]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, caffe
ine, capsaicin, MK-801) had no significant effect on [H-3]gabapentin bindin
g. However, ruthenium red, a relatively nonselective calcium channel ligand
, was found to robustly modulate [H-3]gabapentin binding. Ruthenium red slo
wed the association and dissociation kinetics of [H-3]gabapentin while incr
easing the number of detectable binding sites. Spermine and MgCl2, which al
so bind to calcium channels and modulate [H-3]gabapentin binding, were foun
d to act in a similar manner. These findings support the contention that th
e principal endogenous binding site for gabapentin is a calcium channel; th
ey characterize the nature of the allosteric interaction of spermine, MgCl2
and ruthenium red with this binding site; and they suggest possible mechan
isms by which gabapentin may modulate calcium channel function and ultimate
ly produce therapeutic actions. (C) 2000 Elsevier Science Ltd. All rights r
eserved.