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Feedback Regulation of G Protein-Coupled Receptor Signaling

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Feedback Regulation of G Protein-Coupled Receptor Signaling G Model YSCDB-1903; No. of Pages 10 ARTICLE IN PRESS Seminars in Cell & Developmental Biology xxx (2016) xxx–xxx Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology j ournal homepage: www.elsevier.com/locate/semcdb Review Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins a b a,∗ Joseph B. Black , Richard T. Premont , Yehia Daaka a Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, United States b Department of Medicine, Duke University Medical Center, Durham, NC 27710, United States a r a t b i c s t l e i n f o r a c t Article history: GPCRs are ubiquitous in mammalian cells and present intricate mechanisms for cellular signaling Received 23 October 2015 and communication. Mechanistically, GPCR signaling was identified to occur vectorially through het- Accepted 19 December 2015 erotrimeric G proteins that are negatively regulated by GRK and arrestin effectors. Emerging evidence Available online xxx highlights additional roles for GRK and Arrestin partners, and establishes the existence of interconnected feedback pathways that collectively define GPCR signaling. GPCRs influence cellular dynamics and can Keywords: mediate pathologic development, such as cancer and cardiovascular remolding. Hence, a better under- GPCR standing of their overall signal regulation is of great translational interest and research continues to G protein Arrestin exploit the pharmacologic potential for modulating their activity. GRK © 2016 Elsevier Ltd. All rights reserved. Signal transduction Biased signaling Contents 1. Introduction . 00 2. 7TMR/GPCR signaling overview . 00 2.1. Diversity . 00 2.2. Structure and classification . 00 2.3. G protein signaling mechanism . 00 2.4. G protein classification . 00 2.5. GPCR functional classification. .00 3. 7TMR/GPCR dynamics . 00 3.1. Receptor desensitization . 00 3.2. Receptor sequestration . 00 3.3. Receptor downregulation . 00 3.4. Constitutive activity . 00 3.5. Agonist and antagonist dynamics . 00 4. Signal termination: GRK, arrestin, and G protein switching . 00 4.1. Regulated GPCR-G protein coupling and G protein switching . 00 4.2. GRK signal termination. .00 4.3. Arrestin signal termination . 00 4.4. Arrestin GPCR feedback regulation . 00 5. GRK and arrestin-mediated signaling . 00 5.1. Non-canonical GRK activity . 00 5.2. Arrestin-mediated signaling . 00 5.3. GPCR biased signaling . 00 6. Perspective . 00 References . 00 ∗ Corresponding author. E-mail address: ydaaka@ufl.edu (Y. Daaka). http://dx.doi.org/10.1016/j.semcdb.2015.12.015 1084-9521/© 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: J.B. Black, et al., Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins, Semin Cell Dev Biol (2016), http://dx.doi.org/10.1016/j.semcdb.2015.12.015 G Model YSCDB-1903; No. of Pages 10 ARTICLE IN PRESS 2 J.B. Black et al. / Seminars in Cell & Developmental Biology xxx (2016) xxx–xxx 1. Introduction and the ␤2-adrenergic receptor (␤2AR). Family B is defined by sequence homology to secretin and glucagon receptors. Expres- Cellular differentiation is a hallmark of multicellular orga- sion of family B receptors is localized largely to gastrointestinal nisms that is essential for specialization at the cell, tissue, and and neuronal tissue. The smallest canonical 7TMR subfamily, fam- organ level. Specialization promotes organismal development and ily C receptors are neuromodulatory metabotropic glutamate and survival by permitting cells to differentiate into cellular lin- GABAB receptors. This family is expressed in both the peripheral eages that possess unique properties, such as sensation, secretion, and central nervous systems and is responsible for processing absorption, or conductivity [1]. Multicellular organisms coordinate diverse signals, such as pain, anxiety, and memory formation. these activities to sustain homeostasis. Cell surface receptors and Non-canonical receptors include those of the Frizzled family that signaling molecules represent a pivotal mechanism for overcom- recognize Wnt ligands, or the Hedgehog co-receptor Smoothened. ing this challenge by facilitating cellular communication [2,3]. The These receptors exert their effect through G protein independent Seven Transmembrane Span Receptors (7TMR)/G Protein-Coupled mechanisms [13]. Receptors (GPCRs) family represents the largest superfamily of cell surface receptors, with over 800 distinct receptors encoded 2.3. G protein signaling mechanism within the human genome [4]. This review highlights the biologic role and regulation of 7TMR/GPCR and their interacting proteins, G protein activation is dependent primarily upon GPCR stim- while reviewing their structure, classification, and mechanism ulation. GPCRs remain mostly inactive on the cell surface until of action. bound by a cognate activating agonist and initiate G protein activa- tion (Fig. 1). A GPCR’s corresponding G protein generally remains inactive until GPCR activation. In their inactive conformation, G 2. 7TMR/GPCR signaling overview proteins exist in a heterotrimeric state: the constituent ␣-subunit, bound to GDP, is tightly associated with the ␤␥-subunit.
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