title: Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor.
abstract: 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 Ca(2+)-dependent Cl- currents and atropine (2 microM) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC50 values of 177 +/- 32 microM to 272 +/- 26 microM in different experiments. Responses to ACh (200 microM) 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 microM). 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 microM while that for (-)-MK-801 was 14 +/- 3 microM. 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.
authors.affiliation: Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Briggs
authors.forename: D G
authors.initials: DG
authors.lastname: McKenna
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008464:Mecamylamine / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D002038:Bungarotoxins; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C054634:methyllycaconitine; D008464:Mecamylamine; D016291:Dizocilpine Maleate; D000157:Aconitine