RT Journal Article
SR Electronic
T1 Sazetidine-A Is a Potent and Selective Agonist at Native and Recombinant α4β2 Nicotinic Acetylcholine Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1838
OP 1843
DO 10.1124/mol.108.045104
VO 73
IS 6
A1 Ruud Zwart
A1 Anna L. Carbone
A1 Mirko Moroni
A1 Isabel Bermudez
A1 Adrian J. Mogg
A1 Elizabeth A. Folly
A1 Lisa M. Broad
A1 Andrew C. Williams
A1 Deyi Zhang
A1 Chunjin Ding
A1 Beverly A. Heinz
A1 Emanuele Sher
YR 2008
UL http://molpharm.aspetjournals.org/content/73/6/1838.abstract
AB Sazetidine-A has been recently proposed to be a “silent desensitizer” of α4β2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes α4β2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to distinguish between the role of activation and desensitization of α4β2 nAChRs in mediating the central nervous system effects of nicotine itself, as well as those of new nicotinic drugs. We were surprised to find that sazetidine-A potently and efficaciously stimulated nAChR-mediated dopamine release from rat striatal slices, which is mediated by α4β2* and α6β2* subtypes of nAChR. The agonist effects on native striatal nAChRs prompted us to re-examine the effects of sazetidine-A on recombinant α4β2 nAChRs in more detail. We expressed the two alternative stoichiometries of α4β2 nAChR in Xenopus laevis oocytes and investigated the agonist properties of sazetidine-A on both α4(2)β2(3) and α4(3)β2(2) nAChRs. We found that sazetidine-A potently activated both stoichiometries of α4β2 nAChR: it was a full agonist on α4(2)β2(3) nAChRs, whereas it had an efficacy of only 6% on α4(3)β2(2) nAChRs. In contrast to what has been published before, we therefore conclude that sazetidine-A is an agonist of native and recombinant α4β2 nAChRs but shows differential efficacy on α4β2 nAChRs subtypes. The American Society for Pharmacology and Experimental Therapeutics