Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex
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Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K+-induced [Ca2+]i increase in fura-2-loaded human neocortical synaptosomes (IC50=17 占for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [3H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K+-induced [Ca2+]i increase was prevented by the P/Q-type voltage-gated Ca2+ channel blocker ?-agatoxin IVA. The a2d-1, a2d-2, and a2d-3 subunits of voltage-gated Ca2+ channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K+-evoked release of [3H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca2+ channel a2d subunit to selectively attenuate depolarization-induced Ca2+ influx of presynaptic P/Q-type Ca2+ channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.