Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor

Responses of the human alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) expressed in Xenopus laevis oocytes were quantified in the presence of barium (10 mM) to prevent secondary activation of Ca2+-dependent Cl- currents and atropine (2 mu M) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC(50) values of 177+/-32 mu M to 272+/-26 mu M in different experiments. Responses to ACh (200 mu M) were blocked by the nAChR antagonists alpha-bungarotoxin (IC50=0.54+/-0.04 nM), methyllycaconitine (IC50=0.64+/-0.08 nM) and mecamylamine (IC50=1.8+/-02 mu M) Additionally, MK-801, a non-competitive blocker of N-methyl-D-aspartate (NMDA) sensitive glutamate receptor channels, inhibited the human alpha 7 nAChR. This effect was not stereoselective; the IC50 for (+)-MK-801 was 15+/-3 mu M while that for (-)-MK-801 was 14+/-3 mu M The inhibition by MK-801, in contrast to methyllycaconitine, was dependent upon cell potential, consistent with a mechanism involving channel blockade. The inhibition by MK-801 reversed slowly (time constant approximately 20 min) compared to that by methyllycaconitine (100% recovery within 10 min). However, MK-801 did not appear to be trapped in the channel because the recovery from inhibition showed little dependence upon stimulation rate or cell potential. Thus, MK-801 acted as a non-stereoselective alpha 7 nAChR inhibitor that was only about 8-fold less potent than the nAChR antagonist mecamylamine and probably acted through channel blockade. (C) 1996 Elsevier Science Ltd.