Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Biogenic amine receptors play critical roles in regulating behavior and physiology, particularly within the central nervous system, in both vertebrates and invertebrates. These receptors belong to the G-protein coupled receptor (GPCR) family and interact with endogenous bioamine ligands, such as dopamine, serotonin, and epinephrine, and they are targeted by a wide array of pharmaceuticals. Despite these receptors’ clear clinical and biological importance, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality, structurally-curated sequence alignment of vertebrate biogenic amine receptors. We demonstrate that aligning GPCR sequences without considering structure produces an alignment with substantial error, whereas a structurally-aware approach greatly improves alignment accuracy. Moreover, we show that phylogenetic inference with our structurally-curated alignment offers dramatic improvements over a structurally-naive alignment. Using the structural alignment and its corresponding phylogeny, we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.

An Evolutionarily Conserved G-Protein Coupled Receptor Family, SREB, Expressed in the Central Nervous System

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2000.2829 ◽

2000 ◽

Vol 272 (2) ◽

pp. 576-582 ◽

Cited By ~ 41

Author(s):

Mitsuyuki Matsumoto ◽

Tetsu Saito ◽

Jun Takasaki ◽

Masazumi Kamohara ◽

Toru Sugimoto ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

G Protein ◽

G Protein Coupled Receptor ◽

Evolutionarily Conserved ◽

The Central Nervous System ◽

G Protein Coupled ◽

Cloning of a novel biogenic amine receptor-like G protein-coupled receptor expressed in human brain

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/s0167-4781(01)00289-5 ◽

2001 ◽

Vol 1521 (1-3) ◽

pp. 66-72 ◽

Cited By ~ 7

Author(s):

Stefan Cikos ◽

Paul Gregor ◽

Juraj Koppel

Keyword(s):

Human Brain ◽

G Protein ◽

Biogenic Amine ◽

G Protein Coupled Receptor ◽

Biogenic Amine Receptor ◽

Melatonin MT1 and MT2 Receptors Exhibit Distinct Effects in the Modulation of Body Temperature across the Light/Dark Cycle

International Journal of Molecular Sciences ◽

10.3390/ijms20102452 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2452 ◽

Cited By ~ 8

Author(s):

Martha López-Canul ◽

Seung Hyun Min ◽

Luca Posa ◽

Danilo De Gregorio ◽

Annalida Bedini ◽

...

Keyword(s):

Body Temperature ◽

Receptor Antagonist ◽

Partial Agonist ◽

Receptor Subtypes ◽

Dark Phase ◽

Light Phase ◽

Dark Cycle ◽

Simultaneous Activation ◽

Type 3 ◽

Melatonin (MLT) is a neurohormone that regulates many physiological functions including sleep, pain, thermoregulation, and circadian rhythms. MLT acts mainly through two G-protein-coupled receptors named MT1 and MT2, but also through an MLT type-3 receptor (MT3). However, the role of MLT receptor subtypes in thermoregulation is still unknown. We have thus investigated the effects of selective and non-selective MLT receptor agonists/antagonists on body temperature (Tb) in rats across the 12/12-h light–dark cycle. Rectal temperature was measured every 15 min from 4:00 a.m. to 9:30 a.m. and from 4:00 p.m. to 9:30 p.m., following subcutaneous injection of each compound at either 5:00 a.m. or 5:00 p.m. MLT (40 mg/kg) had no effect when injected at 5 a.m., whereas it decreased Tb during the light phase only when injected at 5:00 p.m. This effect was blocked by the selective MT2 receptor antagonist 4P-PDOT and the non-selective MT1/MT2 receptor antagonist, luzindole, but not by the α1/MT3 receptors antagonist prazosin. However, unlike MLT, neither the selective MT1 receptor partial agonist UCM871 (14 mg/kg) nor the selective MT2 partial agonist UCM924 (40 mg/kg) altered Tb during the light phase. In contrast, UCM871 injected at 5:00 p.m. increased Tb at the beginning of the dark phase, whereas UCM924 injected at 5:00 a.m. decreased Tb at the end of the dark phase. These effects were blocked by luzindole and 4P-PDOT, respectively. The MT3 receptor agonist GR135531 (10 mg/kg) did not affect Tb. These data suggest that the simultaneous activation of both MT1 and MT2 receptors is necessary to regulate Tb during the light phase, whereas in a complex but yet unknown manner, they regulate Tb differently during the dark phase. Overall, MT1 and MT2 receptors display complementary but also distinct roles in modulating circadian fluctuations of Tb.

Mapping the Heart

Microscopy Today ◽

10.1017/s155192951000043x ◽

2010 ◽

Vol 18 (4) ◽

pp. 6-8

Author(s):

Stephen W. Carmichael

Keyword(s):

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

G Protein Coupled Receptors ◽

Receptor Subtypes ◽

Cardiac Muscle Cells ◽

Guanine Nucleotide Binding Protein ◽

The Common ◽

Guanine Nucleotide Binding ◽

First Time ◽

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

GRKs as Modulators of Neurotransmitter Receptors

Cells ◽

10.3390/cells10010052 ◽

2020 ◽

Vol 10 (1) ◽

pp. 52

Author(s):

Eugenia V. Gurevich ◽

Vsevolod V. Gurevich

Keyword(s):

G Protein ◽

General Model ◽

G Protein Coupled Receptors ◽

Receptor Internalization ◽

Neurotransmitter Receptors ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Receptor Kinase ◽

G Protein Coupled ◽

Homologous Desensitization

Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known.

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 ◽

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.

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations—A Short Overview

International Journal of Molecular Sciences ◽

10.3390/ijms22116141 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6141

Author(s):

Teodora Larisa Timis ◽

Ioan Alexandru Florian ◽

Sergiu Susman ◽

Ioan Stefan Florian

Keyword(s):

Immune Cells ◽

Arteriovenous Malformations ◽

Intracranial Aneurysms ◽

Immune Cell ◽

Vascular Malformations ◽

Cerebral Injury ◽

Future Research ◽

Mortality And Morbidity ◽

The Central Nervous System ◽

The Brain

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.

Characterization of the G protein-coupled receptor family SREB across fish evolution

Scientific Reports ◽

10.1038/s41598-021-91590-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Timothy S. Breton ◽

William G. B. Sampson ◽

Benjamin Clifford ◽

Anyssa M. Phaneuf ◽

Ilze Smidt ◽

...

Keyword(s):

G Protein ◽

Genomic Structure ◽

Integrated Approach ◽

Orphan Receptor ◽

Specific Gene ◽

Testicular Development ◽

Brain Expression ◽

And Function ◽

G Protein Coupled ◽

AbstractThe SREB (Super-conserved Receptors Expressed in Brain) family of G protein-coupled receptors is highly conserved across vertebrates and consists of three members: SREB1 (orphan receptor GPR27), SREB2 (GPR85), and SREB3 (GPR173). Ligands for these receptors are largely unknown or only recently identified, and functions for all three are still beginning to be understood, including roles in glucose homeostasis, neurogenesis, and hypothalamic control of reproduction. In addition to the brain, all three are expressed in gonads, but relatively few studies have focused on this, especially in non-mammalian models or in an integrated approach across the entire receptor family. The purpose of this study was to more fully characterize sreb genes in fish, using comparative genomics and gonadal expression analyses in five diverse ray-finned (Actinopterygii) species across evolution. Several unique characteristics were identified in fish, including: (1) a novel, fourth euteleost-specific gene (sreb3b or gpr173b) that likely emerged from a copy of sreb3 in a separate event after the teleost whole genome duplication, (2) sreb3a gene loss in Order Cyprinodontiformes, and (3) expression differences between a gar species and teleosts. Overall, gonadal patterns suggested an important role for all sreb genes in teleost testicular development, while gar were characterized by greater ovarian expression that may reflect similar roles to mammals. The novel sreb3b gene was also characterized by several unique features, including divergent but highly conserved amino acid positions, and elevated brain expression in puffer (Dichotomyctere nigroviridis) that more closely matched sreb2, not sreb3a. These results demonstrate that SREBs may differ among vertebrates in genomic structure and function, and more research is needed to better understand these roles in fish.

Development of a Novel SNAP-Epitope Tag/Near-Infrared Imaging Assay to Quantify G Protein-Coupled Receptor Degradation in Human Cells

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220979793 ◽

2021 ◽

pp. 247255522097979

Author(s):

Kyung-Soon Lee ◽

Edelmar Navaluna ◽

Nicole M. Marsh ◽

Eric M. Janezic ◽

Chris Hague

Keyword(s):

G Protein ◽

Adrenergic Receptor ◽

Near Infrared ◽

Human Cells ◽

Receptor Subtypes ◽

G Protein Coupled Receptor ◽

Functional Responses ◽

Epitope Tag ◽

Nir Imaging ◽

We have developed a novel reporter assay that leverages SNAP-epitope tag/near-infrared (NIR) imaging technology to monitor G protein-coupled receptor (GPCR) degradation in human cell lines. N-terminal SNAP-tagged GPCRs were subcloned and expressed in human embryonic kidney (HEK) 293 cells and then subjected to 24 h of cycloheximide (CHX)-chase degradation assays to quantify receptor degradation half-lives ( t1/2) using LICOR NIR imaging–polyacrylamide gel electrophoresis (PAGE) analysis. Thus far, we have used this method to quantify t1/2 for all nine adrenergic (ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3), five somatostatin (SSTR1, SSTR2, SSTR3, SSTR4, SSTR5), four chemokine (CXCR1, CXCR2, CXCR3, CXCR5), and three 5-HT2 (5HT2A, 5HT2B, 5HT2C) receptor subtypes. SNAP-GPCR-CHX degradation t1/2 values ranged from 0.52 h (ADRA1D) to 5.5 h (SSTR3). On the contrary, both the SNAP-tag alone and SNAP-tagged and endogenous β-actin were resistant to degradation with CHX treatment. Treatment with the proteasome inhibitor bortezomib produced significant but variable increases in SNAP-GPCR protein expression levels, indicating that SNAP-GPCR degradation primarily occurs through the proteasome. Remarkably, endogenous β2-adrenergic receptor/ADRB2 dynamic mass redistribution functional responses to norepinephrine were significantly decreased following CHX treatment, with a time course equivalent to that observed with the SNAP-ADRB2 degradation assay. We subsequently adapted this assay into a 96-well glass-bottom plate format to facilitate high-throughput GPCR degradation screening. t1/2 values quantified for the α1-adrenergic receptor subtypes (ADRA1A, ADRA1B, ADR1D) using the 96-well-plate format correlated with t1/2 values quantified using NIR-PAGE imaging analysis. In summary, this novel assay permits precise quantitative analysis of GPCR degradation in human cells and can be readily adapted to quantify degradation for any membrane protein of interest.