Inhibition of human alpha 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors.
1. Human alpha 7 nicotinic acetylcholine (ACh) receptors were expressed in Xenopus oocytes and the effects of the N-methyl-D-aspartate (NMDA) receptor open channel blockers memantine and cerestat on this receptor were examined using two-electrode voltage-clamp recordings and 125I-alpha-bungarotoxin (125I-alpha-bgtx) binding. 2. Memantine and cerestat produced complete inhibition of ACh-induced inward currents with affinities similar to that reported for native NMDA receptors. Cerestat, IC50 1.7 (-1; +2) microm, was more potent than memantine, IC50 5 (-3;+8) microM, and the effects of both drugs were fully and rapidly reversible. 3. Inhibition of alpha 7 receptor function was voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of 125I-alpha-bgtx to alpha 7 receptors, suggesting that the effects of memantine or cerestat are noncompetitive. 4. These results provide evidence that human alpha 7 receptors are inhibited by memantine and cerestat and suggest that caution should be applied when using these compounds to study systems in which NMDA and nACh receptors co-exist.
Maskell
Peter D
PD
School of Biological and Molecular Sciences, Oxford Brookes University, Oxford OX3 0BP.
Speder
Pauline
P
Newberry
Nigel R
NR
Bermudez
Isabel
I
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D008559:Memantine / 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*; D014981:Xenopus
D002038:Bungarotoxins; D002121:Calcium Channel Blockers; D006146:Guanidines; D007457:Iodine Radioisotopes; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C079779:aptiganel; D000109:Acetylcholine; D008559:Memantine