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BBA - Biomembranes (v.1768, #4)

Editorial Board (pp. ii).

G protein-coupled receptors, signaling mechanisms and pathophysiological relevance by Pablo V. Escribá (pp. 747-747).

Seven transmembrane receptors—A brief personal retrospective by Robert J. Lefkowitz (pp. 748-755).

Receptors have fascinated biologists for more than a century and they have fascinated me for the entirety of my own research career. The seven transmembrane receptors, also known as G protein coupled receptors, represent the largest of the several families of plasma membrane receptors, comprising more than a thousand genes and regulating virtually all known physiological processes in mammals. Moreover, they represent one of the commonest targets of currently used drugs. I have spent the entirety of my research career working on these receptors. Here I set down some personal reflections on the evolution of the field during the past 35 years, hanging the thread of the story on some of the work from my own laboratory.

Keywords: G protein-coupled receptor; β-adrenergic receptor; GRK, β-arrestin; Ligand binding; Desensitization

The discovery of signal transduction by G proteins. A personal account and an overview of the initial findings and contributions that led to our present understanding by Lutz Birnbaumer (pp. 756-771).

The realization that there existed a G-protein coupled signal transduction mechanism developed gradually and was initially the result of an ill fated quest for uncovering the mechanism of action of insulin, followed by a refocused research in many laboratories, including mine, on how GTP acted to increase hormonal stimulation of adenylyl cyclase. Independent research into how light-activated rhodopsin triggers a response in photoreceptor cells of the retina and the attendant biochemical studies joined midway and, without the left hand knowing well what the right hand was doing, preceded classical G protein research in identifying the molecular players responsible for signal transduction by G proteins.

Expansion of signal transduction by G proteins by Lutz Birnbaumer (pp. 772-793).

The first 15 years, or so, brought the realization that there existed a G protein coupled signal transduction mechanism by which hormone receptors regulate adenylyl cyclases and the light receptor rhodopsin activates visual phosphodiesterase. Three G proteins, Gs, Gi and transducin (T) had been characterized as αβγ heterotrimers, and Gsα-GTP and Tα-GTP had been identified as the sigaling arms of Gs and T. These discoveries were made using classical biochemical approaches, and culminated in the purification of these G proteins. The second 15 years, or so, are the subject of the present review. This time coincided with the advent of powerful recombinant DNA techniques. Combined with the classical approaches, the field expanded the repertoire of G proteins from 3 to 16, discovered the superfamily of seven transmembrane G protein coupled receptors (GPCRs) – which is not addressed in this article – and uncovered an amazing repertoire of effector functions regulated not only by αGTP complexes but also by βγ dimers. Emphasis is placed in presenting how the field developed with the hope of conveying why many of the new findings were made.

G protein coupled receptor structure and activation by Brian K. Kobilka (pp. 794-807).

G protein coupled receptors (GPCRs) are remarkably versatile signaling molecules. The members of this large family of membrane proteins are activated by a spectrum of structurally diverse ligands, and have been shown to modulate the activity of different signaling pathways in a ligand specific manner. In this manuscript I will review what is known about the structure and mechanism of activation of GPCRs focusing primarily on two model systems, rhodopsin and the β₂ adrenoceptor.

Keywords: Abbreviations; β; ₂; AR; beta 2 adrenoceptor; GPCR; G protein coupled receptor; TM; transmembraneGPCR; 7TM; Structure; Conformational change; Efficacy

G-protein coupled receptor structure by Philip L. Yeagle; Arlene D. Albert (pp. 808-824).

Because of their central role in regulation of cellular function, structure/function relationships for G-protein coupled receptors (GPCR) are of vital importance, yet only recently have sufficient data been obtained to begin mapping those relationships. GPCRs regulate a wide range of cellular processes, including the senses of taste, smell, and vision, and control a myriad of intracellular signaling systems in response to external stimuli. Many diseases are linked to GPCRs. A critical need exists for structural information to inform studies on mechanism of receptor action and regulation. X-ray crystal structures of only one GPCR, in an inactive state, have been obtained to date. However considerable structural information for a variety of GPCRs has been obtained using non-crystallographic approaches. This review begins with a review of the very earliest GPCR structural information, mostly derived from rhodopsin. Because of the difficulty in crystallizing GPCRs for X-ray crystallography, the extensive published work utilizing alternative approaches to GPCR structure is reviewed, including determination of three-dimensional structure from sparse constraints. The available X-ray crystallographic analyses on bovine rhodopsin are reviewed as the only available high-resolution structures for any GPCR. Structural information available on ligand binding to several receptors is included. The limited information on excited states of receptors is also reviewed. It is concluded that while considerable basic structural information has been obtained, more data are needed to describe the molecular mechanism of activation of a GPCR.

Keywords: GPCR; Structure; Membrane protein

G protein-coupled receptor dimerisation: Molecular basis and relevance to function by Graeme Milligan (pp. 825-835).

The belief that G protein-coupled receptors exist and function as monomeric, non-interacting species has been largely supplanted in recent years by evidence, derived from a range of approaches, that indicate they can form dimers and/or higher-order oligomeric complexes. Key roles for receptor homo-dimerisation include effective quality control of protein folding prior to plasma membrane delivery and interactions with hetero-trimeric G proteins. Growing evidence has also indicated the potential for many co-expressed G protein-coupled receptors to form hetero-dimers/oligomers. The relevance of this to physiology and function is only beginning to be unravelled but may offer great potential for more selective therapeutic intervention.

Keywords: G protein-coupled receptor; Dimerisation; Signal transduction

Lipid–protein interactions in GPCR-associated signaling by Pablo V. Escribá; Philip B. Wedegaertner; Félix M. Goñi; Oliver Vögler (pp. 836-852).

Signal transduction via G-protein-coupled receptors (GPCRs) is a fundamental pathway through which the functions of an individual cell can be integrated within the demands of a multicellular organism. Since this family of receptors first discovered, the proteins that constitute this signaling cascade and their interactions with one another have been studied intensely. In parallel, the pivotal role of lipids in the correct and efficient propagation of extracellular signals has attracted ever increasing attention. This is not surprising given that most of the signal transduction machinery is membrane-associated and therefore lipid-related. Hence, lipid–protein interactions exert a considerable influence on the activity of these proteins. This review focuses on the post-translational lipid modifications of GPCRs and G proteins (palmitoylation, myristoylation, and isoprenylation) and their significance for membrane binding, trafficking and signaling. Moreover, we address how the particular biophysical properties of different membrane structures may regulate the localization of these proteins and the potential functional consequences of this phenomenon in signal transduction. Finally, the interactions that occur between membrane lipids and GPCR effector enzymes such as PLC and PKC are also considered.

Keywords: Abbreviations; Arg; arginin; cPH; C-terminal half of pleckstrin homology; Cys; cysteine; DAG; diacylglycerol; DHA; docosahexaenoic acid; GPCR; G-protein-coupled receptor; GRK; G-protein-coupled receptor kinase; H; _II; hexagonal II (inverted hexagonal); His; histidin; Ins(1,4,5)P; ₃; inositol 1,4,5-trisphosphate; l; _o; liquid-ordered; LH/hCG receptor; luteinizing hormone/human chorionic gonadotropin receptor; NMR; nuclear magnetic resonance; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PI; phosphoinositide; PH; pleckstrin homology; PKC; protein kinase C; PLC; phospholipase C; RACK; receptor for activated C kinase; Ser; serine; Trp; tryptophan; TRPC3; transient receptor potential 3Signal transduction; Membrane structure; G-protein-coupled receptor; G protein; Palmitoylation; Myristoylation; Isoprenylation; Farnesyl; Geranylgeraniol; Phospholipase C; Protein kinase C

Regulation of G protein-coupled receptor export trafficking by Chunmin Dong; Catalin M. Filipeanu; Matthew T. Duvernay; Guangyu Wu (pp. 853-870).

G protein-coupled receptors (GPCRs) constitute a superfamily of cell-surface receptors which share a common topology of seven transmembrane domains and modulate a variety of cell functions through coupling to heterotrimeric G proteins by responding to a vast array of stimuli. The magnitude of cellular response elicited by a given signal is dictated by the level of GPCR expression at the plasma membrane, which is the balance of elaborately regulated endocytic and exocytic trafficking. This review will cover recent advances in understanding the molecular mechanism underlying anterograde transport of the newly synthesized GPCRs from the endoplasmic reticulum (ER) through the Golgi to the plasma membrane. We will focus on recently identified motifs involved in GPCR exit from the ER and the Golgi, GPCR folding in the ER and the rescue of misfolded receptors from within, GPCR-interacting proteins that modulate receptor cell-surface targeting, pathways that mediate GPCR traffic, and the functional role of export in controlling GPCR signaling.

Keywords: G protein-coupled receptor; Intracellular trafficking; Export; Sorting and targeting; Biosynthesis; Endoplasmic reticulum; Golgi; Folding; ER export motif; ER retention motif; ER chaperone; Chemical chaperone; Pharmacological chaperone; GPCR-interacting protein; Signal transduction

Dopamine D3 receptor ligands—Recent advances in the control of subtype selectivity and intrinsic activity by Frank Boeckler; Peter Gmeiner (pp. 871-887).

Various pharmacological studies have implicated the dopamine D₃ receptor as an interesting therapeutic target in the treatment of different neurological disorders. Because of these putative therapeutic applications, D₃ receptor ligands with diverse intrinsic activities have been an active field of research in recent years. Separation of purely D₃-mediated drug effects from effects produced by interactions with similar biogenic amine receptors allows to verify the therapeutic impact of D₃ receptors and to reduce possible side-effects caused by “promiscuous” receptor interactions. The requirement to gain control of receptor selectivity and in particular subtype selectivity has been a challenging task in rational drug discovery for quite a few years. In this review, recently developed structural classes of D₃ ligands are discussed, which cover a broad spectrum of intrinsic activities and show interesting selectivities.

Keywords: Dopamine D3 receptor; Agonist; Antagonist; Structure activity relationship; Rational drug discovery; G protein-coupled receptor

Dynamic phospholipid signaling by G protein-coupled receptors by Paschal A. Oude Weernink; Li Han; Karl H. Jakobs; Martina Schmidt (pp. 888-900).

G protein-coupled receptors (GPCRs) control a variety of fundamental cellular processes by regulating phospholipid signaling pathways. Essential for signaling by a large number of receptors is the hydrolysis of the membrane phosphoinositide PIP₂ by phospholipase C (PLC) into the second messengers IP₃ and DAG. Many receptors also stimulate phospholipase D (PLD), leading to the generation of the versatile lipid, phosphatidic acid. Particular PLC and PLD isoforms take differential positions in receptor signaling and are additionally regulated by small GTPases of the Ras, Rho and ARF families. It is now recognized that the PLC substrate, PIP₂, has signaling capacity by itself and can, by direct interaction, affect the activity and subcellular localization of PLD and several other proteins. As expected, the synthesis of PIP₂ by phosphoinositide 5-kinases is tightly regulated as well. In this review, we present an overview of how these signaling pathways are governed by GPCRs, explain the molecular basis for the spatially and temporally organized, highly dynamic quality of phospholipid signaling, and point to the functional connection of the pathways.

Keywords: Abbreviations; DAG; diacylglycerol; EGF; epidermal growth factor; ERK; extracellular signal-regulated kinase; GAP; GTPase-activating protein; GEF; guanine nucleotide exchange factor; GPCR; G protein-coupled receptor; GTPγS; guanosine 5′-; 0; -(3-thio)-triphosphate; IP; ₃; inositol-1,4,5-trisphosphate; LPA; lysophosphatidic acid; PA; phosphatidic acid; PDGF; platelet-derived growth factor; PH; pleckstrin homology; PX; phox homology; PI3K; phosphoinositide 3-kinase; PIP5K; phosphoinositide 5-kinase; PIP; ₂; phosphatidylinositol-4,5-bisphosphate; PIP; ₃; phosphatidylinositol-3,4,5-trisphosphate; PKA; protein kinase A; PKC; protein kinase C; PLC; phospholipase C; PLD; phospholipase D; PTX; pertussis toxin; RA; Ras-binding domain; RGS; regulators of G protein signaling; RTK; receptor tyrosine kinase; SH; Src homologyGPCR; Phospholipase C; Phospholipase D; PIP; ₂; Phosphoinositide 5-kinase; Small GTPase

The cell biology of Smo signalling and its relationships with GPCRs by Ana Ruiz-Gómez; Cristina Molnar; Helena Holguín; Federico Mayor Jr.; Jose F. de Celis (pp. 901-912).

The Smoothened (Smo) signalling pathway participates in many developmental processes, contributing to the regulation of gene expression by controlling the activity of transcription factors belonging to the Gli family. The key elements of the pathway were identified by means of genetic screens carried out in Drosophila, and subsequent analysis in other model organisms revealed a high degree of conservation in both the proteins involved and in their molecular interactions. Recent analysis of the pathway, using a combination of biochemical and cell biological approaches, is uncovering the intricacies of Smo signalling, placing its elements in particular cellular compartments and qualifying the molecular processes involved. These include the synthesis, secretion and diffusion of the ligand, the activation of the receptor and the modifications in the activity of nuclear effectors. In this review we discuss recent advances in understanding biochemical and cellular aspects of Smo signalling, with particular focus in the similarities in the mechanism of signal transduction between Smo and other transmembrane proteins belonging to the G- Protein coupled receptors superfamily (GPCR).

Keywords: Hh signalling; Smoothened; GPCR; GRKs; β-arrestin

The G protein-coupled receptor kinase (GRK) interactome: Role of GRKs in GPCR regulation and signaling by Catalina Ribas; Petronila Penela; Cristina Murga; Alicia Salcedo; Carlota García-Hoz; María Jurado-Pueyo; Ivette Aymerich; Federico Mayor Jr. (pp. 913-922).

G protein-coupled receptor kinases (GRKs) and arrestins are key participants in the canonical pathways leading to phosphorylation-dependent GPCR desensitization, endocytosis, intracellular trafficking and resensitization as well as in the modulation of important intracellular signaling cascades by GPCR. Novel studies have revealed a phosphorylation-independent desensitization mechanism operating through their RGS-homology (RH) domain and the recent determination of the crystal structures of GRK2 and GRK6 has uncovered interesting details on the structure–function relationships of these kinases. Emerging evidence indicates that the activity of GRKs is tightly modulated by mechanisms including phosphorylation by different kinases and interaction with several cellular proteins such as calmodulin, caveolin or RKIP. In addition, GRKs are involved in multiple interactions with non-receptor proteins (PI3K, Akt, GIT or MEK) that point to novel GRK cellular roles. In this article, our purpose is to describe the ever increasing map of functional interactions for GRK proteins as a basis to better understand its contribution to cellular processes.

Keywords: GRKs; GPCR; Arrestin; G protein; Kinase

Lysophospholipid receptors: Signalling, pharmacology and regulation by lysophospholipid metabolism by Dagmar Meyer zu Heringdorf; Karl H. Jakobs (pp. 923-940).

The lysophospholipids, sphingosine-1-phosphate (S1P), lysophosphatidic acid (LPA), sphingosylphosphorylcholine (SPC) and lysophosphatidylcholine (LPC), activate diverse groups of G-protein-coupled receptors that are widely expressed and regulate decisive cellular functions. Receptors of the endothelial differentiation gene family are activated by S1P (S1P_1–5) or LPA (LPA_1–3); two more distantly related receptors are activated by LPA (LPA_4/5); the GPR_3/6/12 receptors have a high constitutive activity but are further activated by S1P and/or SPC; and receptors of the OGR1 cluster (OGR1, GPR4, G2A, TDAG8) appear to be activated by SPC, LPC, psychosine and/or protons. G-protein-coupled lysophospholipid receptors regulate cellular Ca²⁺ homoeostasis and the cytoskeleton, proliferation and survival, migration and adhesion. They have been implicated in development, regulation of the cardiovascular, immune and nervous systems, inflammation, arteriosclerosis and cancer. The availability of S1P and LPA at their G-protein-coupled receptors is regulated by enzymes that generate or metabolize these lysophospholipids, and localization plays an important role in this process. Besides FTY720, which is phosphorylated by sphingosine kinase-2 and then acts on four of the five S1P receptors of the endothelial differentiation gene family, other compounds have been identified that interact with more ore less selectivity with lysophospholipid receptors.

Keywords: Abbreviations; [Ca; ²⁺; ]; _i; intracellular free Ca; ²⁺; concentration; DGPP 8:0; dioctanoylglycerol pyrophosphate; EDG; endothelial differentiation gene; ERK; extracellular signal-regulated kinase; FAP; fatty alcohol phosphate; GPCR; G-protein-coupled receptor; LPA; lysophosphatidic acid; LPC; lysophosphatidylcholine; LPP; lipid phosphate phosphatase; NGF; nerve growth factor; PDGF; platelet-derived growth factor; PLA; phospholipase A; PLC; phospholipase C; PLD; phospholipase D; PPARγ; peroxisome proliferator-activated receptor-γ; PTX; pertussis toxin; S1P; sphingosine-1-phosphate; SPC; sphingosylphosphoryl choline; SPP; sphingosine-1-phosphate phosphatase; THI; 2-acetyl-4-tetrahydroxybutylimidazoleG-protein-coupled receptor; Lysophospholipid; Sphingosine-1-phosphate; Lysophosphatidic acid; Sphingosine kinase; Autotaxin

G protein-coupled receptors control NMDARs and metaplasticity in the hippocampus by John F. MacDonald; Michael F. Jackson; Michael A. Beazely (pp. 941-951).

Long-term potentiation (LTP) and long-term depression (LTD) are the major forms of functional synaptic plasticity observed at CA1 synapses of the hippocampus. The balance between LTP and LTD or “metaplasticity” is controlled by G-protein coupled receptors (GPCRs) whose signal pathways target the N-methyl-D-asparate (NMDA) subtype of excitatory glutamate receptor. We discuss the protein kinase signal cascades stimulated by Gαq and Gαs coupled GPCRs and describe how control of NMDAR activity shifts the threshold for the induction of LTP.

Keywords: NMDA receptor; G-protein coupled receptor; PKA; PKC; Src kinases; Synaptic efficacy; Longterm potentiation

Regulation of CXCR4 signaling by John M. Busillo; Jeffrey L. Benovic (pp. 952-963).

The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoiesis, and immune response. Recent evidence has highlighted the role of CXCR4 in a variety of diseases including HIV, cancer, and WHIM syndrome. Importantly, the involvement of CXCR4 in cancer metastasis and WHIM syndrome appears to be due to dysregulation of the receptor leading to enhanced signaling. Herein we review what is currently known regarding the regulation of CXCR4 and how dysregulation contributes to disease progression.

Keywords: CXCR4; Receptor regulation; Phosphorylation; Cancer; WHIM syndrome; Signaling

G protein-coupled receptor systems and their lipid environment in health disorders during aging by Regina Alemany; Javier S. Perona; José M. Sánchez-Dominguez; Emilio Montero; Julio Cañizares; Ricardo Bressani; Pablo V. Escribá; Valentina Ruiz-Gutierrez (pp. 964-975).

Cells, tissues and organs undergo phenotypic changes and deteriorate as they age. Cell growth arrest and hyporesponsiveness to extrinsic stimuli are all hallmarks of senescent cells. Most such external stimuli received by a cell are processed by two different cell membrane systems: receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). GPCRs form the largest gene family in the human genome and they are involved in most relevant physiological functions. Given the changes observed in the expression and activity of GPCRs during aging, it is possible that these receptors are directly involved in aging and certain age-related pathologies. On the other hand, both GPCRs and G proteins are associated with the plasma membrane and since lipid–protein interactions regulate their activity, they can both be considered to be sensitive to the lipid environment. Changes in membrane lipid composition and structure have been described in aged cells and furthermore, these membrane changes have been associated with alterations in GPCR mediated signaling in some of the main health disorders in elderly subjects. Although senescence could be considered a physiologic process, not all aging humans develop the same health disorders. Here, we review the involvement of GPCRs and their lipid environment in the development of the major human pathologies associated with aging such as cancer, neurodegenerative disorders and cardiovascular pathologies.

Keywords: G protein-coupled receptor; Aging; Human pathology; Signaling protein; Lipid membrane composition; Fatty acid

G protein-coupled receptors in major psychiatric disorders by Lisa A. Catapano; Husseini K. Manji (pp. 976-993).

Although the molecular mechanisms underlying psychiatric illnesses such as depression, bipolar disorder and schizophrenia remain incompletely understood, there is increasing clinical, pharmacologic, and genetic evidence that G protein-coupled receptors (GPCRs) play critical roles in these disorders and their treatments. This perspectives paper reviews and synthesizes the available data. Dysfunction of multiple neurotransmitter and neuropeptide GPCRs in frontal cortex and limbic-related regions, such as the hippocampus, hypothalamus and brainstem, likely underlies the complex clinical picture that includes cognitive, perceptual, affective and motoric symptoms. The future development of novel agents targeting GPCR signaling cascades remains an exciting prospect for patients refractory to existing therapeutics.

Keywords: G protein-coupled receptors (GPCRs); Depression; Bipolar disorder; Schizophrenia; Serotonin; Dopamine; Glutamate

Impact of GPCRs in clinical medicine: Monogenic diseases, genetic variants and drug targets by Paul A. Insel; Chih-Min Tang; Ines Hahntow; Martin C. Michel (pp. 994-1005).

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common. Genetic variants, especially single nucleotide polymorphisms (SNPs), show substantial heterogeneity in frequency among different GPCRs but have not been evaluated for some GPCR. Many therapeutic agonists and antagonists target GPCR and show inter-subject variability in terms of efficacy and toxicity. For most of those agents, it remains an open question whether genetic variation in primary sequence of the GPCR is an important contributor to such inter-subject variability, although this is an active area of investigation.

Keywords: GPCR mutation; Human disease; Nephrogenic diabetes insipidus; Retinitis pigmentosa

Cardiac GPCRs: GPCR signaling in healthy and failing hearts by Natasha C. Salazar; Juhsien Chen; Howard A. Rockman (pp. 1006-1018).

G protein-coupled receptors (GPCRs) are widely implicated in human heart disease, making them an important target for cardiac drug therapy. The most commonly studied and clinically targeted cardiac GPCRs include the adrenergic, angiotensin, endothelin, and adenosine receptors. Treatment options focusing on the complex and integrated signaling pathways of these GPCRs are critical for the understanding and amelioration of heart disease. The focus of this review is to highlight the most commonly studied and clinically targeted cardiac GPCRs, placing emphasis on their common signaling components implicated in cardiac disease.

Keywords: G protein-coupled receptors; Signaling; Beta-Arrestin; Endocytosis

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BBA - Biomembranes (v.1768, #4)