An ER-resident membrane protein complex regulates nicotinic acetylcholine receptor subunit composition at the synapse.
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.
Almedom
Ruta B
RB
Department of Biochemistry, Chemistry and Pharmacy, Johann Wolfgang Goethe-University, Institute of Biochemistry, Frankfurt, Germany.
Liewald
Jana F
JF
Hernando
Guillermina
G
Schultheis
Christian
C
Rayes
Diego
D
Pan
Jie
J
Schedletzky
Thorsten
T
Hutter
Harald
H
Bouzat
Cecilia
C
Gottschalk
Alexander
A
D000200:Action Potentials; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D011978:Receptors, Nicotinic