Article
- The EMBO Journal (2009) 28, 2636 - 2649
- doi:10.1038/emboj.2009.204
Published online: 16 July 2009
Subject Categories:
An ER-resident membrane protein complex regulates nicotinic acetylcholine receptor subunit composition at the synapse
Ruta B Almedom1,5, Jana F Liewald1,5, Guillermina Hernando2, Christian Schultheis1, Diego Rayes2, Jie Pan3, Thorsten Schedletzky1, Harald Hutter3, Cecilia Bouzat2 and Alexander Gottschalk1,4
- Department of Biochemistry, Chemistry and Pharmacy, Johann Wolfgang Goethe-University, Institute of Biochemistry, Frankfurt, Germany
- Instituto de Investigaciones Bioquimicas, Universidad Nacional del Sur-CONICET, Bahia Blanca, Argentina
- Department of Biological Sciences, Simon Fraser University, University Drive, Burnaby, British Columbia, Canada
- Cluster of Excellence Frankfurt—Macromolecular Complexes (CEF-MC), Goethe-University, Frankfurt, Germany
Correspondence to:
Alexander Gottschalk, Department of Biochemistry, Johann Wolfgang Goethe-University Frankfurt, Cluster of Excellence Frankfurt—Macromolecular Complexes, Max-von-Laue-Str. 9, Frankfurt 60438, Germany. Tel.: +49 69 7982 9261; Fax: +49 69 7982 9495; E-mail: a.gottschalk@em.uni-frankfurt.de
5These authors contributed equally to this work
Received 14 January 2009; Accepted 18 June 2009
Abstract
Nicotinic acetylcholine receptors (nAChRs) are homo- or heteropentameric ligand-gated ion channels mediating excitatory neurotransmission and muscle activation. Regulation of nAChR subunit assembly and transfer of correctly assembled pentamers to the cell surface is only partially understood. Here, we characterize an ER transmembrane (TM) protein complex that influences nAChR cell-surface expression and functional properties in Caenorhabditis elegans muscle. Loss of either type I TM protein, NRA-2 or NRA-4 (nicotinic receptor associated), affects two different types of muscle nAChRs and causes in vivo resistance to cholinergic agonists. Sensitivity to subtype-specific agonists of these nAChRs is altered differently, as demonstrated by whole-cell voltage-clamp of dissected adult muscle, when applying exogenous agonists or after photo-evoked, channelrhodopsin-2 (ChR2) mediated acetylcholine (ACh) release, as well as in single-channel recordings in cultured embryonic muscle. These data suggest that nAChRs desensitize faster in nra-2 mutants. Cell-surface expression of different subunits of the 'levamisole-sensitive' nAChR (L-AChR) is differentially affected in the absence of NRA-2 or NRA-4, suggesting that they control nAChR subunit composition or allow only certain receptor assemblies to leave the ER.
Keywords:
- channelrhodopsin-2,
- nAChR biogenesis,
- Nicalin,
- NOMO,
- single-channel properties
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