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Untranslated Region-Dependent Exclusive Expression of High-Sensitivity Subforms of 42 and 32 Nicotinic Acetylcholine Receptors

Neuroscience Research, Abbott Laboratories, Abbott Park, Illinois (C.A.B., E.J.G., C.B.P., R.T., M.D.M., C.S.S.); and Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (M.J.M.)

42 nicotinic acetylcholine receptors (nAChRs) are recognized as the principal nicotine binding site in brain. Recombinant 42 nAChR demonstrate biphasic concentration-response relationships with low- and high-EC₅₀ components. This study shows that untranslated regions (UTR) can influence expression of high-sensitivity subforms of 42 and 32 nAChR. Oocytes injected with 4 and 2 RNA lacking UTR expressed biphasic concentration-response relationships for acetylcholine with high-sensitivity EC₅₀ values of 0.5 to 2.5 µM (14–24% of the population) and low-sensitivity EC₅₀ values of 110 to 180 µM (76–86%). In contrast, message with UTR expressed exclusively the high-sensitivity 42 nAChR subform with an acetylcholine EC₅₀ value of 2.2 µM. Additional studies revealed pharmacological differences between high- and low-sensitivity 42 subforms. Whereas the antagonists dihydro--erythroidine (IC₅₀ of 3–6 nM) and methyllycaconitine (IC₅₀ of 40–135 nM) were not selective between high- and low-sensitivity 42, chlorisondamine, mecamylamine, and d-tubocurarine were, respectively, 100-, 8-, and 5-fold selective for the 42 subform with low sensitivity to acetylcholine. Conversely, agonists that selectively activated the high-sensitivity 42 subform with respect to efficacy as well as potency were identified. Furthermore, two of these agonists were shown to activate mouse brain 42 as well as the ferret high-sensitivity 42 expressed in Xenopus laevis oocytes. With the use of UTR-containing RNA, exclusive expression of a novel high-sensitivity 32 nAChR was also achieved. These studies 1) provide further evidence for the existence of multiple subforms of 42 nAChR, 2) extend that to 32 nAChR, 3) demonstrate UTR influence on 2-containing nAChR properties, and 4) reveal compounds that interact with 42 in a subform-selective manner.

Address correspondence to: Dr. Clark A. Briggs, Neuroscience Research, R47W Bldg. AP9A-3, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064. E-mail: clark.briggs{at}abbott.com

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