Details

Autor(en) / Beteiligte

• Yeatman, Holly R.
• Lane, J. Robert
• Choy, Kwok Ho Christopher
• Lambert, Nevin A.
• Sexton, Patrick M.
• Christopoulos, Arthur
• Canals, Meritxell

Titel

Allosteric Modulation of M1 Muscarinic Acetylcholine Receptor Internalization and Subcellular Trafficking

Ist Teil von

• The Journal of biological chemistry, 2014-05, Vol.289 (22), p.15856-15866

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Allosteric modulators are an attractive approach to achieve receptor subtype-selective targeting of G protein-coupled receptors. Benzyl quinolone carboxylic acid (BQCA) is an unprecedented example of a highly selective positive allosteric modulator of the M1 muscarinic acetylcholine receptor (mAChR). However, despite favorable pharmacological characteristics of BQCA in vitro and in vivo, there is limited evidence of the impact of allosteric modulation on receptor regulatory mechanisms such as β-arrestin recruitment or receptor internalization and endocytic trafficking. In the present study we investigated the impact of BQCA on M1 mAChR regulation. We show that BQCA potentiates agonist-induced β-arrestin recruitment to M1 mAChRs. Using a bioluminescence resonance energy transfer approach to monitor intracellular trafficking of M1 mAChRs, we show that once internalized, M1 mAChRs traffic to early endosomes, recycling endosomes and late endosomes. We also show that BQCA potentiates agonist-induced subcellular trafficking. M1 mAChR internalization is both β-arrestin and G protein-dependent, with the third intracellular loop playing an important role in the dynamics of β-arrestin recruitment. As the global effect of receptor activation ultimately depends on the levels of receptor expression at the cell surface, these results illustrate the need to extend the characterization of novel allosteric modulators of G protein-coupled receptors to encapsulate the consequences of chronic exposure to this family of ligands. The effects of allosteric modulators on G protein-coupled receptor trafficking are largely unknown. The allosteric ligand BQCA modulates M1 mAChR arrestin recruitment and receptor trafficking. M1 mAChR trafficking is arrestin- and G protein-dependent and modulated by BQCA. The impact of allosteric modulators on receptor trafficking needs to be assessed when considering this family of ligands as potential chronic therapies.