TY - JOUR T1 - Pharmacology of α-Conotoxin MII-Sensitive Subtypes of Nicotinic Acetylcholine Receptors Isolated by Breeding of Null Mutant Mice JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1563 LP - 1571 DO - 10.1124/mol.106.031492 VL - 71 IS - 6 AU - Outi Salminen AU - Jennifer A. Drapeau AU - J. Michael McIntosh AU - Allan C. Collins AU - Michael J. Marks AU - Sharon R. Grady Y1 - 2007/06/01 UR - http://molpharm.aspetjournals.org/content/71/6/1563.abstract N2 - Subtypes of nicotinic acetylcholine receptors (nAChR) containing α6 subunits comprise 25 to 30% of the presynaptic nAChRs expressed in striatal dopaminergic terminals in rodents and 70% in monkeys. This class of receptors, potentially important in nicotine addiction, binds α-conotoxin MII (α-CtxMII) with high affinity and is heterogeneous, consisting of several subtypes in mice, possibly an important consideration for the design of compounds that selectively activate or antagonize the α6 subclass of nAChRs. Selected-null mutant mice were bred to generate isolated subtypes of α6β2* nAChRs expressed in vivo for assessing pharmacology of α6β2* nAChRs. Binding to striatal membranes and function in synaptosomes from (α4–/–)(β3+/+) and (α4–/–)(β3–/–) mice were measured and compared with wild-type (α4+/+)(β3+/+) mice. Gene deletions (α4 and β3) decreased binding of 125I-α-CtxMII without affecting affinity for α-CtxMII or inhibition of α-CtxMII binding by epibatidine or nicotine. Deletion of the α4 subunit substantially increased EC50 values for both nicotine- and cytisine-stimulated α-CtxMII-sensitive dopamine release from striatal synaptosomes. A further increase in EC50 values was seen upon the additional deletion of the β3 subunit. The data indicate that one α-CtxMII-sensitive nAChR subtype, prevalent on wild-type dopaminergic terminals, has the lowest EC50 for a nicotine-mediated function so far measured in mice. In conclusion, the gene deletion strategy enabled isolation of α6* subtypes, and these nAChR subtypes exhibited differential activation by nicotine and cytisine. The American Society for Pharmacology and Experimental Therapeutics ER -