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J. Biol. Chem., Vol. 280, Issue 26, 24568-24575, July 1, 2005

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Identification and Structural Determination of the M₃ Muscarinic Acetylcholine Receptor Basolateral Sorting Signal^*

Heidi A. Iverson, David Fox, III¶, Laurie S. Nadler||, Rachel E. Klevit¶, and Neil M. Nathanson**

From the Departments of Pharmacology and ^¶Biochemistry, University of Washington, Seattle, Washington 98195

Muscarinic acetylcholine receptors comprise a family of G-protein-coupled receptors that display differential localization in polarized epithelial cells. We identify a seven-residue sequence, Ala²⁷⁵-Val²⁸¹, in the third intracellular loop of the M₃ muscarinic receptor that mediates dominant, position-independent basolateral targeting in Madin-Darby canine kidney cells. Mutational analyses identify Glu²⁷⁶, Phe²⁸⁰, and Val²⁸¹ as critical residues within this sorting motif. Phe²⁸⁰ and Val²⁸¹ comprise a novel dihydrophobic sorting signal as mutations of either residue singly or together with leucine do not disrupt basolateral targeting. Conversely, Glu²⁷⁶ is required and cannot be substituted with alanine or aspartic acid. A 19-amino acid peptide representing the M₃ sorting signal and surrounding sequence was analyzed via two-dimensional nuclear magnetic resonance spectroscopy. Solution structures show that Glu²⁷⁶ resides in a type IV -turn and the dihydrophobic sequence Phe²⁸⁰Val²⁸¹ adopts either a type I or IV -turn.

Received for publication, February 3, 2005 , and in revised form, April 15, 2005.

^* This research was supported by National Institutes of Health Grants RO1 NS26920, T32GM07750, T32GM008268-17, and PO1 HL44948. 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.

Both authors contributed equally to this work.

^|| Present address: Division of Neuroscience and Basic Behavioral Science, NIMH, National Institutes of Health, Bethesda, MD 20892.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of Washington, K536A Health Sciences Bldg., Box 357750, 1959 NE Pacific, Seattle, WA 98195-7750. Tel.: 206-543-9457; Fax: 206-616-4230; E-mail: nathanso{at}u.washington.edu.

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