Arrestin-Dependent Localization of Phosphodiesterases
Many G-protein-coupled receptors trigger the synthesis of cAMP in order to transduce signals from the membrane into the cell cytoplasm. As stimulation of each receptor type results in a specific physiological outcome, compartmentalization of proteins that
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Contents 1 Phosphodiesterases Underpin Compartmentalized cAMP Responses . . . . . . . . . . . . . . . . . . . . . 2 Discovery of the Interaction Between PDE4 Enzymes and β-Arrestin . . . . . . . . . . . . . . . . . . . 3 Molecular Characterization of the PDE4–β-Arrestin Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Involvement of the PDE4D5–β-Arrestin Complex in Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Involvement of the PDE4–β-Arrestin Complex in Immune Cell Response . . . . . . . . . . . . . . 6 PDE4–β-Arrestin Complex in the Desensitization of GPCRs in the Brain . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Many G-protein-coupled receptors trigger the synthesis of cAMP in order to transduce signals from the membrane into the cell cytoplasm. As stimulation of each receptor type results in a specific physiological outcome, compartmentalization of proteins that make, break, and are activated by cAMP underpin receptor-specific responses. Until 2002, it was thought that static compartmentalization of phosphodiesterase 4 (PDE4), conferred by N-terminal targeting sequences, was one way to shape intricate cAMP gradients that formed after receptor activation. Discovery of the PDE4–β-arrestin complex represented a major breakthrough in cAMP signaling, as it spurred the initial realization that PDE4s could be transported to sites of high cAMP to orchestrate destruction of the second messenger at the same time as the receptor’s signal to the G-protein is silenced. This chapter charts the scientific process that led to the discovery and characterization of the PDE4–β-arrestin interaction and discusses the known functions of this signaling complex. Keywords Phosphodiesterase type 4 (PDE4) • Cyclic AMP • Compartmentalization • Peptide array • Protein kinase A (PKA) • β-arrestin M.J. Willis • G.S. Baillie (*) Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G128QQ, UK e-mail: [email protected] V.V. Gurevich (ed.), Arrestins - Pharmacology and Therapeutic Potential, Handbook of Experimental Pharmacology 219, DOI 10.1007/978-3-642-41199-1_15, © Springer-Verlag Berlin Heidelberg 2014
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1 Phosphodiesterases Underpin Compartmentalized cAMP Responses Cell surface receptors sense the extracellular environment and react to chemical cues such as hormones, neurotransmitters, or signaling peptides by stimulating the creation of “second messengers” that act to trigger intracellular cell signaling cascades. One such second messenger, cyclic AMP (cAMP), is produced by adenylyl cyclase (Cooper and Crossthwaite 2006) and acts via one of three known effector proteins: cAMP-dependent protein kinase [also known as protein kinase A (PKA)] (Taylor et al. 2012), cyclic nu
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