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J. Biol. Chem., Vol. 278, Issue 45, 44033-44040, November 7, 2003

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The Effects of 3 Subunit Incorporation on the Pharmacology and Single Channel Properties of Oocyte-expressed Human 34 Neuronal Nicotinic Receptors^*

James P. Boorman, Marco Beato, Paul J. Groot-Kormelink, Steven D. Broadbent, and Lucia G. Sivilotti¶

From the Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London, WC1N 1AX United Kingdom

We compared the main properties of human recombinant 343 neuronal nicotinic receptors with those of 34 receptors, expressed in Xenopus oocytes. 3 incorporation decreased the channel mean open time (from 5.61 to 1.14 ms, after approximate correction for missed gaps) and burst length. There was also an increase in single channel slope conductance from 28.8 picosiemens (34) to 46.7 picosiemens (343; in low divalent external solution). On the other hand, the calcium permeability (determined by a reversal potential method in chloride-depleted oocytes) and the pharmacological properties of 3-containing receptors differed little from those of 34. The main pharmacological difference in 343 "triplet" receptors was a 3-fold decrease in the potency of lobeline relative to acetylcholine. Nevertheless, there was no change in the rank order of potency for agonists (epibatidine >> lobeline > cytisine, 1,1-dimethyl-4-phenylpiperazinium iodide, nicotine > acetylcholine > carbachol for both receptors; measured at low agonist concentrations). Sensitivity to the competitive antagonists trimetaphan (0.2–1 µM) and dihydro--erythroidine (30 µM) was similar for the two combinations, with a Schild K_B for trimetaphan of 76 and 66 nM on 34 and 343, respectively. The change in single channel conductance confirms that 3 replaces a 4 subunit in the pentamer. The absence of pronounced differences in the pharmacological profile of the triplet receptor argues against a role for the 3 subunit in the formation of agonist binding sites, whereas the changes in channel kinetics suggest an important effect on receptor gating. The shortening of the burst length of 3-containing receptors implies that any synaptic currents mediated by such channels would have faster decay kinetics.

Received for publication, November 18, 2002 , and in revised form, July 24, 2003.

^* This work was supported by Wellcome Trust Project Grants 055524 and 064652, Medical Research Council Cooperative Grant G9819400 Ph.D. studentship (to S. D. B.), and a School of Pharmacy Millennium Ph.D. Studentship (to J. P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Dept. of Biology, University College London, London WC1E 6BT, UK.

Current address: Dept. of Pharmacology, University College of London, London WC1E 6BT, UK.

^¶ To whom correspondence should be addressed. Tel.: 44-20-7679-3693; Fax: 44-20-7679-7298; E-mail: l.sivilotti{at}ucl.ac.uk.

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