Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders

Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor’s downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders.

Download Full-text

Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

10.1101/2020.04.20.052027 ◽

2020 ◽

Cited By ~ 4

Author(s):

Charlotte Avet ◽

Arturo Mancini ◽

Billy Breton ◽

Christian Le Gouill ◽

Alexander S. Hauser ◽

...

Keyword(s):

Plasma Membrane ◽

Drug Discovery ◽

Signaling Pathways ◽

G Protein ◽

G Protein Coupled Receptors ◽

Systems Pharmacology ◽

New Knowledge ◽

Translocation Assay ◽

Multiple Signaling ◽

G Protein Coupled

SUMMARYThe ability of individual G protein-coupled receptors (GPCR) to engage multiple signaling pathways opens opportunities for the development of better drugs. This requires new knowledge and tools to determine the G protein subtypes and βarrestins engaged by a given receptor. Here, we used a new BRET-based effector membrane translocation assay (EMTA) that monitors activation of each Gα protein through the recruitment of selective G protein effectors and βarrestins to the plasma membrane. Profiling of 100 therapeutically relevant GPCR revealed a great diversity of coupling profiles with some receptors displaying exquisite selectivity, whereas others promiscuitely engage all four G protein families. Comparison with existing datasets points to commonalities but also to critical differences between studies. Combining a biosensor subset allowed detecting activity of nearly all GPCR thus providing a new tool for safety screens and systems pharmacology. Overall, this work describes unique resources for studying GPCR function and drug discovery.

Download Full-text

Multiple Signaling Pathways for Platelet-Activating Factor Receptor

Physiology ◽

10.1152/physiologyonline.1992.7.2.72 ◽

1992 ◽

Vol 7 (2) ◽

pp. 72-75

Author(s):

SD Shukla

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Signaling Pathways ◽

G Protein ◽

Platelet Activating Factor ◽

G Protein Coupled Receptors ◽

Kinase C ◽

Paf Receptor ◽

Multiple Signaling ◽

G Protein Coupled

Platelet-activating factor (PAF) receptor is coupled to multiple signaling pathways, including phospholipid turnover via phospholipases C, D, A2;Ca2+ mobilization;and activation of protein kinase C and tyrosine kinase. The cloned receptor shows homology to G protein-coupled receptors. These developments highlight receptor functions of this novel phospholipid agonist.

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

Constitutive signal bias mediated by the human GHRHR splice variant 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106606118 ◽

2021 ◽

Vol 118 (40) ◽

pp. e2106606118

Author(s):

Zhaotong Cong ◽

Fulai Zhou ◽

Chao Zhang ◽

Xinyu Zou ◽

Huibing Zhang ◽

...

Keyword(s):

Splice Variant ◽

Human Growth ◽

Bound State ◽

G Protein Coupled Receptors ◽

Cancer Cell Proliferation ◽

Downstream Signaling ◽

Functional Studies ◽

Dynamics Simulations ◽

Protein Molecular Dynamics ◽

G Protein Coupled

Alternative splicing of G protein–coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone–releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates Gs while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the apo state or GHRH-bound state in complex with the Gs protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, Gs versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.

Download Full-text

Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0906695106 ◽

2010 ◽

Vol 107 (5) ◽

pp. 2319-2324 ◽

Cited By ~ 141

Author(s):

Adolfo Rivero-Müller ◽

Yen-Yin Chou ◽

Inhae Ji ◽

Svetlana Lajic ◽

Aylin C. Hanyaloglu ◽

...

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Luteinizing Hormone Receptor ◽

Wild Type ◽

Gpcr Signaling ◽

Physiological Relevance ◽

Biosynthesis Activation ◽

Mutant Receptors ◽

G Protein Coupled

G protein–coupled receptors (GPCRs) are ubiquitous mediators of signaling of hormones, neurotransmitters, and sensing. The old dogma is that a one ligand/one receptor complex constitutes the functional unit of GPCR signaling. However, there is mounting evidence that some GPCRs form dimers or oligomers during their biosynthesis, activation, inactivation, and/or internalization. This evidence has been obtained exclusively from cell culture experiments, and proof for the physiological significance of GPCR di/oligomerization in vivo is still missing. Using the mouse luteinizing hormone receptor (LHR) as a model GPCR, we demonstrate that transgenic mice coexpressing binding-deficient and signaling-deficient forms of LHR can reestablish normal LH actions through intermolecular functional complementation of the mutant receptors in the absence of functional wild-type receptors. These results provide compelling in vivo evidence for the physiological relevance of intermolecular cooperation in GPCR signaling.

Download Full-text

US28: HCMV’s Swiss Army Knife

Viruses ◽

10.3390/v10080445 ◽

2018 ◽

Vol 10 (8) ◽

pp. 445 ◽

Cited By ~ 22

Author(s):

Benjamin Krishna ◽

William Miller ◽

Christine O’Connor

Keyword(s):

Latent Infection ◽

Viral Latency ◽

Lytic Replication ◽

G Protein Coupled Receptors ◽

Disease States ◽

Cellular Pathways ◽

The Impact ◽

Multiple Signaling ◽

G Protein Coupled ◽

Multifunctional Properties

US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV.

Download Full-text

G-Protein–Coupled Receptors Signaling Pathways in New Antiplatelet Drug Development

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.114.303412 ◽

2015 ◽

Vol 35 (3) ◽

pp. 500-512 ◽

Cited By ~ 41

Author(s):

Paul A. Gurbel ◽

Athan Kuliopulos ◽

Udaya S. Tantry

Keyword(s):

Drug Development ◽

Signaling Pathways ◽

G Protein ◽

G Protein Coupled Receptors ◽

Antiplatelet Drug ◽

G Protein Coupled

Download Full-text

Anaphylactic shock depends on endothelial Gq/G11

Journal of Experimental Medicine ◽

10.1084/jem.20082150 ◽

2009 ◽

Vol 206 (2) ◽

pp. 411-420 ◽

Cited By ~ 65

Author(s):

Hanna Korhonen ◽

Beate Fisslthaler ◽

Alexandra Moers ◽

Angela Wirth ◽

Daniel Habermehl ◽

...

Keyword(s):

Signaling Pathways ◽

Anaphylactic Shock ◽

Platelet Activating Factor ◽

Severe Allergic Reaction ◽

Downstream Signaling ◽

Systemic Anaphylaxis ◽

Multiple Organs ◽

Nitric Oxide Formation ◽

G Protein Coupled

Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein–coupled receptors, which are linked to the heterotrimeric G proteins Gq/G11, G12/G13, and Gi. The role of downstream signaling pathways activated by anaphylactic mediators in defined organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of Gq/G11- and G12/G13-mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq/G11-mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various inflammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial Gαq/Gα11 deficiency. Mice with endothelium-specific Gαq/Gα11 deficiency, but not with Gα12/Gα13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11-mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.

Download Full-text

The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein–coupled receptors

The Journal of Cell Biology ◽

10.1083/jcb.200112026 ◽

2002 ◽

Vol 158 (2) ◽

pp. 221-226 ◽

Cited By ~ 218

Author(s):

Yibing Yan ◽

Kyoko Shirakabe ◽

Zena Werb

Keyword(s):

Signaling Pathways ◽

G Protein ◽

Egf Receptor ◽

Critical Role ◽

G Protein Coupled Receptors ◽

Heparin Binding ◽

Egf Receptors ◽

Gpcr Activation ◽

G Protein Coupled ◽

Stimulation Of

Communication between different signaling pathways enables cells to coordinate the responses to diverse environmental signals. Activation of the transmembrane growth factor precursors plays a critical role in this communication and often involves metalloprotease-mediated proteolysis. Stimulation of G protein–coupled receptors (GPCR) transactivates the EGF receptors (EGFRs), which occurs via a metalloprotease-dependent cleavage of heparin-binding EGF (HB-EGF). However, the metalloprotease mediating the transactivation remains elusive. We show that the integral membrane metalloprotease Kuzbanian (KUZ; ADAM10), which controls Notch signaling in Drosophila, stimulates GPCR transactivation of EGFR. Upon stimulation of the bombesin receptors, KUZ increases the docking and activation of adaptors Src homology 2 domain–containing protein and Gab1 on the EGFR, and activation of Ras and Erk. In contrast, transfection of a protease domain–deleted KUZ, or blocking endogenous KUZ by morpholino antisense oligonucleotides, suppresses the transactivation. The effect of KUZ on shedding of HB-EGF and consequent transactivation of the EGFR depends on its metalloprotease activity. GPCR activation enhances the association of KUZ and its substrate HB-EGF with tetraspanin CD9. Thus, KUZ regulates the relay between the GPCR and EGFR signaling pathways.

Download Full-text