Ligand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1

Jacqueline Flores-Otero, Kwang H. Ahn, Francheska Delgado-Peraza, Ken Mackie, Debra A. Kendall and Guillermo A. Yudowski ()
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Jacqueline Flores-Otero: University of Puerto Rico, Medical Sciences Campus
Kwang H. Ahn: University of Connecticut
Francheska Delgado-Peraza: University of Puerto Rico, Medical Sciences Campus
Ken Mackie: Gill Center for Biomedical Sciences, Indiana University
Debra A. Kendall: University of Connecticut
Guillermo A. Yudowski: University of Puerto Rico, Medical Sciences Campus

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract G protein-coupled receptors (GPCRs) are the major transducers of external stimuli and key therapeutic targets in many pathological conditions. When activated by different ligands, one receptor can elicit multiple signalling cascades that are mediated by G proteins or β-arrestin, a process defined as functional selectivity or ligand bias. However, the dynamic mechanisms underlying β-arrestin signalling remain unknown. Here by studying the cannabinoid receptor 1 (CB1R), we identify ligand-specific endocytic dwell times, that is, the time during which receptors are clustered into clathrin pits together with β-arrestins before endocytosis, as the mechanism controlling β-arrestin signalling. Agonists inducing short endocytic dwell times produce little or no β-arrestin signalling, whereas those eliciting prolonged dwell times induce robust signalling. Remarkably, extending CB1R dwell times by preventing endocytosis substantially increased β-arrestin signalling. These studies reveal how receptor activation translates into β-arrestin signalling and identify a mechanism to control this pathway.

Date: 2014
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DOI: 10.1038/ncomms5589

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