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J. Biol. Chem., Vol. 283, Issue 11, 6826-6831, March 14, 2008

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The 5-HT_3B Subunit Confers Spontaneous Channel Opening and Altered Ligand Properties of the 5-HT₃ Receptor^*

From the Department of Biomedical Sciences, College of Health Sciences, Marquette University, Milwaukee, Wisconsin 53201-1881

Current receptor theory suggests that there is an equilibrium between the inactive (R) and active (R*) conformations of ligand-gated ion channels and G protein-coupled receptors. The actions of ligands in both receptor types could be appropriately explained by this two-state model. Ligands such as agonists and antagonists affect receptor function by stabilizing one or both conformations. The 5-HT₃ receptor is a member of the Cys-loop ligand-gated ion channel superfamily participating in synaptic transmission. Here we show that co-expression of the 5-HT_3A and 5-HT_3B receptor subunits in the human embryonic kidney (HEK) 293 cells results in a receptor that displays a low level of constitutive (or agonist-independent) activity. Furthermore, we also demonstrate that the properties of ligands can be modified by receptor composition. Whereas the 5-hydroxytryptamine (5-HT) analog 5-methoxyindole is a partial agonist at the 5-HT_3A receptor, it becomes a "protean agonist" (functioning as an agonist and an inverse agonist at the same receptor) at the 5-HT_3AB receptor (after the Greek god Proteus, who was able to change his shape and appearance at will). In addition, the 5-HT analog 5-hydroxyindole is a positive allosteric modulator for the liganded active (AR*) conformation of the 5-HT_3A and 5-HT_3AB receptors and a negative allosteric modulator for the spontaneously active (R*) conformation of the 5-HT_3AB receptor, suggesting that the spontaneously active (R*) and liganded active (AR*) conformations are differentially modulated by 5-hydroxyindole. Thus, the incorporation of the 5-HT_3B subunit leads to spontaneous channel opening and altered ligand properties.

Received for publication, September 10, 2007 , and in revised form, December 19, 2007.

^* This work was supported by institutional funds from Marquette University and by National Institutes of Health Grant AA015203 (to R. W. P.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence should be addressed: Dept. of Biomedical Sciences, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881. Tel.: 414-288-6679; Fax: 414-288-6564; E-mail: xiangqun.hu{at}marquette.edu.

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