MK-801 INHIBITION OF NICOTINIC ACETYLCHOLINE-RECEPTOR CHANNELS

MK-801 is a potent inhibitor of the NMDA subtype of glutamate receptors. Single-channel and macroscopic currents indicate that MK-801 also inhibits nicotinic acetylcholine receptors (nAChRs). MK-801 does not significantly increase desensitization of the nAChRs or compete for the ACh binding site. Although there is a slight inhibition of the closed nAChR, the main action of MK-801 is to enter and block the open channel. The voltage dependence for block is consistent with a single binding site within the channel that is 50% of the way through the membrane field. The IC50 for block is 3-mu-M at -70 mV for currents induced by 0.5-mu-M ACh. The data from both single-channel and macroscopic currents can be used to estimate a K(d) (0) of 7-mu-M, which is about 40 times higher than the K(d)(0) for MK-801 binding to the NMDA receptor. The relative potency of tricyclic compounds like MK-801 for various neurotransmitter systems points out that the pharmacologic action of these drugs could involve complicated interactions in vivo.