Inhibition of Ca channel current by luteinizing hormone-releasing hormone (LHRH) was studied in freshly dissociated bullfrog sympathetic ganglion neurons using whole-cell recording. LHRH inhibited up to 80% of the high-threshold Ca channel current with a half-maximally effective concentration of about 20 nM. LHRH inhibited omega-conotoxin- sensitive but not nimodipine-sensitive current and also did not inhibit Bay K 8644-enhanced currents, suggesting that LHRH inhibits N-type but not L-type channels. Inhibition was faster at higher concentrations of LHRH, reaching a limiting time constant of 2 sec at 0.3-3 mM LHRH. The rate of recovery from block (tau approximately 19 sec) was independent of LHRH concentration. Inhibition of N-type current by LHRH was highly sensitive to the gating state of the channel. Though strongly effective if applied when channels were mostly in the resting state, LHRH had little effect if applied rapidly during a long depolarization that opened the channels. Inhibition could be relieved if channels were activated by short, large test depolarizations or by long, smaller depolarizations. The state-dependent properties of LHRH block could be simulated by a model that assumes that inhibition by LHRH results from activated G-proteins binding to N-type channels and that (1) G-protein binding stabilizes closed gating states and (2) activation of G-protein- bound channels destabilizes the binding of the G-protein to the channel.