期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 22, 页码 15856-15866出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.536672
关键词
Allosteric Regulation; Arrestin; G Protein-coupled Receptor (GPCR); Receptor Endocytosis; Trafficking; GPCR Regulation; Allosteric Modulator
资金
- National Health and Medical Research Council [519461, APP1011796]
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 M-1 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 -arrestin recruitment or receptor internalization and endocytic trafficking. In the present study we investigated the impact of BQCA on M-1 mAChR regulation. We show that BQCA potentiates agonist-induced -arrestin recruitment to M-1 mAChRs. Using a bioluminescence resonance energy transfer approach to monitor intracellular trafficking of M-1 mAChRs, we show that once internalized, M-1 mAChRs traffic to early endosomes, recycling endosomes and late endosomes. We also show that BQCA potentiates agonist-induced subcellular trafficking. M-1 mAChR internalization is both -arrestin and G protein-dependent, with the third intracellular loop playing an important role in the dynamics of -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.
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