Trafficking of G Protein–Coupled Receptors

Abstract

Abstract-G protein-coupled receptors (GPCRs) play an integral role in the signal transduction of an enormous array of biological phenomena, thereby serving to modulate at a molecular level almost all components of human biology. This role is nowhere more evident than in cardiovascular biology, where GPCRs regulate such core measures of cardiovascular function as heart rate, contractility, and vascular tone. GPCR/ligand interaction initiates signal transduction cascades, and requires the presence of the receptor at the plasma membrane. Plasma membrane localization is in turn a function of the delivery of a receptor to and removal from the cell surface, a concept defined most broadly as receptor trafficking. This review illuminates our current view of GPCR trafficking, particularly within the cardiovascular system, as well as highlights the recent and provocative finding that components of the GPCR trafficking machinery can facilitate GPCR signaling independent of G protein activation. Key Words: GPCR Ⅲ trafficking Ⅲ GPCR kinase (GRK) Ⅲ ␤-arrestin Ⅲ 7-transmembrane receptors G protein-coupled receptors (GPCRs) are central mediators of nearly all aspects of cardiovascular biology. GPCRs were originally identified as receptors capable of coupling to specific guanine nucleotide-binding proteins (G proteins), thereby transducing an extracellular signal to an intracellular effector, although more recently, several GPCRs have been demonstrated to signal via G protein-independent mechanisms both in vitro and in vivo. 1 As a family of proteins, GPCRs share common structural features, including seven membrane-spanning domains, and thus are alternatively referred to as 7-transmembrane receptors. GPCRs are the largest superfamily of cell-surface receptors, accounting for approximately 2% of the human genome. 2 Further, ligands directed at GPCRs (primarily agonists and antagonists) represent the largest family of pharmacological agents, accounting for nearly 30% of current clinical pharmaceutical agents available. 3 Both hormones and neurotransmitters exert their effects on the cardiovascular system via GPCRs. Examples of GPCRs with well-ascribed roles in cardiovascular biology include the ␤ 1 -and ␤ 2 -adrenergic receptors (ARs), the ␣ 1 -and ␣ 2 -ARs, the M 2 -and M 3 -muscarinic acetylcholine receptors, the angiotensin II (Ang II) receptors, the endothelin receptors, the adenosine receptor, the thrombin receptor, and the vasopressin receptor.Over the past nearly 3 decades, a wealth of information has revealed much about the signaling properties of this family of seven membrane-spanning receptors. Much work has focused on revealing the ways in which the GPCRs regulate discrete effector molecules including adenylyl cyclase, phospholipases, and ion channels. Still further work has shed light on Original

Rapid resensitization of purinergic receptor function in human platelets

“…Recently, we showed that both P2Y 1 and P2Y 12 receptor responses desensitize in human platelets [4], in agreement with the observed desensitization of platelet responses following prolonged exposure to ADP [5][6][7]. Mechanisms underlying desensitization are complex and can involve phosphorylation of the receptor, uncoupling from G proteins, internalization, and ultimately intracellular downregulation [3,[8][9][10][11][12]. We have recently discovered that ADP pretreatment promotes P2Y 1 and P2Y 12 receptor phosphorylation, desensitization, and internalization by different kinase-dependent mechanisms [4,13].…”

“…In this study, we examine if purinergic responses can resensitize following receptor desensitization. The mechanism by which the resensitization of many GPCRs is achieved is thought to be the agonist-stimulated internalization of receptors to an intracellular membrane compartment (endosomes) enriched in a GPCR-specific phosphatase activity [8,10] followed by recycling to the cell membrane. Therefore, we also examined if receptor internalization, dephosphorylation, and recycling are required for resensitization of purinergic responsiveness.…”

Reprogramming of G protein-coupled receptor recycling and signaling by a kinase switch

“…This is especially relevant for signaling receptors, given that relatively small changes in rates of receptor sorting into the recycling pathway can cause significant changes in surface receptors, and hence in cellular sensitivity (1)(2)(3). Our knowledge of receptor signaling and trafficking comes mainly from studying examples such as the beta-2 adrenergic receptor (B2AR), a prototypical member of G proteincoupled receptor (GPCR) family, the largest family of signaling receptors (2)(3)(4)(5). B2AR activation initiates surface receptor removal and transport to endosomes, causing cellular desensitization (6,7).…”

β-Arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2

“…T he trafficking of seven-transmembrane receptors (7TMRs), also known as G protein-coupled receptors (GPCRs), is a tightly regulated process that modulates cell signaling and defines various physiological responses (1). Two homologous mammalian proteins, ␤-arrestin1 and ␤-arrestin2, have been established as primary endocytic and signaling adaptors for a large number of 7TMRs as well as other types of cell surface receptors (2).…”