The subunit composition and pharmacology of alpha-Conotoxin MII-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay.
The subunit composition and pharmacology of alpha-Conotoxin MII-binding (alpha-CtxMII) nicotinic acetylcholine receptors (nAChR) was studied by an improved [(125)I]-alpha-CtxMII membrane binding method. This binding method facilitates pharmacological studies that have been difficult to accomplish with [(125)I]-alpha-CtxMII autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding. Binding densities and K(d)-values obtained by this [(125)I]-alpha-CtxMII membrane binding were similar to the values obtained by autoradiography or alpha-CtxMII inhibition of [(125)I]-epibatidine binding, verifying that each of these approaches measures the same nAChR population. Binding results with nAChR subunit-null mutant mice confirm and extend observations from earlier studies: [(125)I]-alpha-CtxMII binding measures two sets of alpha6beta2* nAChR (alpha4alpha6beta2beta3 or alpha6beta2beta3). Most nicotinic agonists and antagonists show monophasic inhibition of [(125)I]-alpha-CtxMII binding, indicating that alpha4alpha6beta2beta3 and alpha6beta2beta3 have similar binding properties. Comparison of the binding and activation profiles of alpha6beta2* nAChR to those of other nAChR subtypes (alpha4beta2* and beta4*) indicates that these receptors have distinctly different pharmacology indicating that it may be possible to target alpha6beta2* nAChR selectively to develop compounds that might be therapeutically useful.
Salminen
Outi
O
Institute for Behavioral Genetics, University of Colorado, Boulder, 80309, USA. outi.salminen@helsinki.fi
Whiteaker
Paul
P
Grady
Sharon R
SR
Collins
Allan C
AC
McIntosh
J Michael
JM
Marks
Michael J
MJ
D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001392:Azocines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects*; D020916:Conotoxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics; D011725:Pyridines / Q000493:pharmacokinetics; D011807:Quinolizines / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D000093843:Quinolizidine Alkaloids
D000109:Acetylcholine; D000470:Alkaloids; D001384:Azetidines; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020916:Conotoxins; D007456:Iodine Isotopes; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C104288:A 85380; C098872:alpha-conotoxin MII; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine