Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 28, Issue 5, Pages 1009-1022Publisher
KARGER
DOI: 10.1159/000335788
Keywords
G protein-coupled receptors; Muscarinic acetylcholine receptors; NPxxY motif; Phospholipase D; Phospholipase C; Monomeric small G proteins; Desensitization
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Funding
- Swedish Research Council [04X-715]
- Torsten and Ragnar Soderberg Foundation
- Hjarnfonden and Marianne and Marcus Wallenberg Foundation
- Ministerio de Ciencia e Innovacion [SAF2008-01462, Consolider-Ingenio CSD2008-00005]
- Catalan Institution for Research and Advanced Studies
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Acetylcholine challenge produces M-3 muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M-3 muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to G alpha(q/11) after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between M3R and ARF1 and also for the formation of the ARF/Rho/beta gamma signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the M-3 muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation. Copyright (C) 2011 S. Karger AG, Basel
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