Modulation of type A GABA receptors (GABA A) by L-type Ca ++ channel blockers was investigated. The dihydropyridines nifedipine and nitrendipine, and the phenylalkylamine verapamil inhibited recombinant rat α1β2γ2 receptors recorded from human embryonic kidney (HEK) 293 cells; nifedipine at low concentrations also elicited modest stimulatory effects on GABA-gated current. The IC 50 for GABA current inhibition was lowest for nitrendipine (17.3±1.3 μM), so subsequent studies were focused on further exploring its mechanism and possible site of action. When co-applied with GABA, nitrendipine had minimal effects on initial current amplitude, but significantly enhanced current decay rate. Nitrendipine-mediated inhibition was subunit-selective, as its IC 50 was 10-fold lower in α1β2 receptors. Nitrendipine's effect in recombinant human α1β2γ2 receptors was similar (IC 50=23.0±1.3 μM) to that observed in rat receptors of the same configuration, indicating the site of action is conserved in the two species. The inhibitory effects were dependent on channel gating, were independent of transmembrane voltage, and were also observed in GABA A receptors recorded from hypothalamic brain slices. The pharmacologic mechanism of inhibition by nitrendipine was non-competitive, indicating it does not act at the GABA binding site. Nitrendipine block was retained in the presence of the benzodiazepine antagonist flumazenil, indicating it does not interact at the benzodiazepine site. The actions of nitrendipine were not affected by a mutation (β2T246F) that confers resistance to the channel blocker picrotoxin, and they were not altered in the presence of the picrotoxin site antagonist α-isopropyl-α-methyl-γ-butyrolactone, demonstrating nitrendipine does not act at the picrotoxin site of the GABA A receptor. Possible interaction of nitrendipine with the Zn ++ site was also eliminated, as mutation of β2 H267 to A, which confers resistance to Zn ++, had no effect on nitrendipine-mediated inhibition. Our data suggest some of the central effects of dihydropyridines may be due to actions at GABA A receptors. Moreover, the effects may be mediated through interaction with a novel modulatory site on the GABA A receptor.