The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

Download Full-text

The Controversial C5a Receptor C5aR2: Its Role in Health and Disease

Journal of Immunology Research ◽

10.1155/2017/8193932 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 8

Author(s):

Ting Zhang ◽

Malgorzata A. Garstka ◽

Ke Li

Keyword(s):

Animal Models ◽

G Protein ◽

Cellular Localization ◽

G Protein Coupled Receptor ◽

C5a Receptor ◽

Intracellular Signals ◽

Health And Disease ◽

Anti Inflammatory ◽

G Protein Coupled

After the discovery of the C5a receptor C5aR1, C5aR2 is the second receptor found to bind C5a and its des-arginine form. As a heptahelical G protein-coupled receptor but devoid of the intracellular Gα signal, C5aR2 is special and confusing. Ramifications and controversies about C5aR2 are under debate since its identification, from putative ligands and cellular localization to intracellular signals and pathological roles in inflammation and immunity. The ruleless and even conflicting pro- or anti-inflammatory role of C5aR2 in animal models of diverse diseases makes one bewildered. This review summarizes reports on C5aR2, tries to clear up available evidence on these four controversial aspects, and delineates C5aR2 function(s). It also summarizes available toolboxes for C5aR2 study.

Download Full-text

Role of estrogen in diastolic dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00859.2013 ◽

2014 ◽

Vol 306 (5) ◽

pp. H628-H640 ◽

Cited By ~ 91

Author(s):

Zhuo Zhao ◽

Hao Wang ◽

Jewell A. Jessup ◽

Sarah H. Lindsey ◽

Mark C. Chappell ◽

...

Keyword(s):

Heart Failure ◽

Diastolic Dysfunction ◽

G Protein ◽

Intracellular Signaling ◽

Diastolic Heart Failure ◽

Left Ventricular ◽

Female Rat ◽

Cardiac Phenotype ◽

G Protein Coupled

The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.

Download Full-text

Oligomerization in Health and Disease: From Enzymes to G Protein-Coupled Receptors

10.1016/s1877-1173(20)x0002-0 ◽

2020 ◽

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Health And Disease ◽

G Protein Coupled

Download Full-text

Adhesion GPCRs in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab046 ◽

2021 ◽

Author(s):

Gabriele Stephan ◽

Niklas Ravn-Boess ◽

Dimitris G Placantonakis

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

The Past ◽

Novel Treatment ◽

The Family ◽

Health And Disease ◽

Basic Biology ◽

G Protein Coupled ◽

Potential Use ◽

Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

Download Full-text

G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

Cells ◽

10.3390/cells10030672 ◽

2021 ◽

Vol 10 (3) ◽

pp. 672

Author(s):

Richard A. Pepermans ◽

Geetanjali Sharma ◽

Eric R. Prossnitz

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Inflammatory Diseases ◽

Therapy Resistance ◽

Breast Cancers ◽

Obesity And Diabetes ◽

Therapeutic Value ◽

Health And Disease ◽

Multiple Cells ◽

G Protein Coupled

Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.

Download Full-text

G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

Download Full-text

Applications of molecular replacement to G protein-coupled receptors

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s090744491301322x ◽

2013 ◽

Vol 69 (11) ◽

pp. 2287-2292 ◽

Cited By ~ 3

Author(s):

Andrew C. Kruse ◽

Aashish Manglik ◽

Brian K. Kobilka ◽

William I. Weis

Keyword(s):

G Protein ◽

Structural Biology ◽

Structural Information ◽

G Protein Coupled Receptors ◽

Integral Membrane Proteins ◽

Molecular Replacement ◽

Gpcr Activation ◽

Health And Disease ◽

Almost All ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are a large class of integral membrane proteins involved in regulating virtually every aspect of human physiology. Despite their profound importance in human health and disease, structural information regarding GPCRs has been extremely limited until recently. With the advent of a variety of new biochemical and crystallographic techniques, the structural biology of GPCRs has advanced rapidly, offering key molecular insights into GPCR activation and signal transduction. To date, almost all GPCR structures have been solved using molecular-replacement techniques. Here, the unique aspects of molecular replacement as applied to individual GPCRs and to signaling complexes of these important proteins are discussed.

Download Full-text

Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0014 ◽

2010 ◽

Vol 45 (1) ◽

pp. 1-8 ◽

Cited By ~ 47

Author(s):

Davide Calebiro ◽

Viacheslav O Nikolaev ◽

Martin J Lohse

Keyword(s):

G Protein ◽

Intracellular Signaling ◽

Current Model ◽

Living Cells ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Optical Methods ◽

Camp Signaling ◽

Gpcr Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

Download Full-text