Effect of MK-801 at the human α7 nicotinic acetylcholine receptor

• Published in: Neuropharmacology 1996, Vol.35 (4), p.407-414
• Main Authors: Briggs, Clark A., McKenna, David G.
• Format: Article
• Language: English
• Subjects: acetylcholine; Acetylcholine nicotinic receptor; Biological and medical sciences; Glutamatergic system (aspartate and other excitatory aminoacids); human; Medical sciences; methyllycaconitine; MK-801; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; oocytes; Pharmacology. Drug treatments; Xenopus laevis; α7 nicotinic receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/0028-3908(96)00006-8

Responses of the human α7 nicotinic acetylcholine receptor (α7 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 μM) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC 50 values of 177 ± 32 μM to 272 ± 26 μM in different experiments. Responses to ACh (200 μM) were blocked by the nAChR antagonists α-bungarotoxin (IC 50 = 0.54 ± 0.04 nM), methyllycaconitine (IC 50 = 0.64 ± 0.08 nM) and mecamylamine (IC 50 = 1.8 ± 02 μM). Additionally, MK-801, a non-competitive blocker of N-methyl- d-aspartate (NMDA) sensitive glutamate receptor channels, inhibited the human α7 nAChR. This effect was not stereoselective; the IC 50 for (+)-MK-801 was 15 ± 3 μM while that for (−)-MK-801 was 14 ± 3 μM. 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 α7 nAChR inhibitor that was only about 8-fold less potent than the nAChR antagonist mecamylamine and probably acted through channel blockade.