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Perspective

Adenosine Receptors Find a New Partner and Move Out

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska

Recent studies of G protein-coupled receptors have highlighted two "new" and interactive elements involved in their function and regulation: their ability to localize to different cell surface and intracellular compartments and their ability to interact with partners other than their classic heterotrimeric G proteins. The effects mediated by these receptors can be markedly different depending on the compartment in which they reside and the partners with which they interact in each compartment. The studies in this issue of Molecular Pharmacology by Milojevi et al. (page 1083) merge these two themes by identifying the ubiquitin-specific protease Usp4 as a partner for the carboxyl-terminal tail of adenosine A_2A receptors and showing that this interaction allows processing and delivery to the cell surface of newly synthesized A_2A receptors, which are otherwise predominantly intracellular. Their studies suggest that the intracellular A_2A receptors are ubiquitinated, presumably because of misfolding and intervention of the "endoplasmic reticulum quality control" mechanism leading to degradation of the receptors by proteasomes. Increasing Usp4 expression stimulates receptor de-ubiquitination and increases cell surface expression of functional receptors. Evidence is presented for tight specificity of this interaction, with another Usp family member failing to rescue A_2A receptors and Usp4 failing to rescue another intracellular receptor. The background and significance of this study are highlighted here, including puzzles that remain to be solved and the potential for pharmacological targeting of such interactions to manipulate the expression, location, and function of G protein-coupled receptors for therapeutic benefit.

Received for publication January 17, 2006.

Accepted for publication January 17, 2006.

Address correspondence to: Dr. Myron L. Toews, Professor, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198-5800. E-mail: mtoews{at}unmc.edu