A key interfacial residue identified with in-cell structure characterization of a class A GPCR dimer

2019 ◽  
Author(s):  
Ju Yang ◽  
Zhou Gong ◽  
Yun-Bi Lu ◽  
Chan-Juan Xu ◽  
Tao-Feng Wei ◽  
...  
Keyword(s):  
Cell Structure ◽  
Structure Characterization ◽  
Transmembrane Helices ◽  
Distance Measurements ◽  
Class A ◽  
Gpcr Dimer ◽  
Interfacial Residue ◽  
Functional Relevance ◽  
And Function ◽  
G Protein Coupled

AbstractG protein coupled receptors (GPCRs) have been shown homo-dimeric. Despite extensive studies, no single residue has been found essential for dimerization. Lacking an efficient method to shift the monomer-dimer equilibrium also makes functional relevance of GPCR dimer elusive. Here, using fluorescence lifetime-based imaging for distance measurements, we characterize the dimeric structure of GPR17, a class A GPCR, in cells. The structure reveals transmembrane helices 5 and 6 the dimer interface, and pinpoints F229 a key residue, mutations of which can render GPR17 monomeric or dimeric. Using the resulting mutants, we show that GPR17 dimer is coupled to both Gαi and Gαq signaling and is internalized, whereas GPR17 monomer is coupled to Gαi signaling only and is not internalized. We further show that residues equivalent to F229 of GPR17 in several other class A GPCRs are also important for dimerization. Our findings thus provide fresh insights into GPCR structure and function.

Insights into the activation mechanism of the visual receptor rhodopsin

2012 ◽  
Vol 40 (2) ◽  
pp. 389-393 ◽  
Author(s):  
Steven O. Smith
Keyword(s):  
Structural Biology ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class A ◽  
Highly Sensitive ◽  
The Common ◽  
Dim Light ◽  
And Function ◽  
G Protein Coupled ◽  
Visual Receptor

Recent advances in the structural biology of GPCRs (G-protein-coupled receptors) have provided insights into their structure and function. Comparisons of the visual and ligand-activated receptors highlight the unique elements of rhodopsin that allow it to function as a highly sensitive dim-light photoreceptor in vertebrates, as well as the common elements that it shares with the large class A GPCR family. However, despite progress, a number of questions remain unanswered about how these receptors are activated.

scholarly journals The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance

2020 ◽  
Vol 44 (10) ◽  
pp. 2124-2136 ◽  
Author(s):  
Tomáš Suchý ◽  
Christian Zieschang ◽  
Yulia Popkova ◽  
Isabell Kaczmarek ◽  
Juliane Weiner ◽  
...  
Keyword(s):  
G Protein ◽  
Lipid Accumulation ◽  
Adipocyte Differentiation ◽  
G Protein Coupled Receptors ◽  
Adipose Tissues ◽  
Functional Relevance ◽  
And Function ◽  
Adhesion Gpcr ◽  
The Impact ◽  
G Protein Coupled

Abstract Background G protein-coupled receptors (GPCR) are well-characterized regulators of a plethora of physiological functions among them the modulation of adipogenesis and adipocyte function. The class of Adhesion GPCR (aGPCR) and their role in adipose tissue, however, is poorly studied. With respect to the demand for novel targets in obesity treatment, we present a comprehensive study on the expression and function of this enigmatic GPCR class during adipogenesis and in mature adipocytes. Methods The expression of all aGPCR representatives was determined by reanalyzing RNA-Seq data and by performing qPCR in different mouse and human adipose tissues under low- and high-fat conditions. The impact of aGPCR expression on adipocyte differentiation and lipid accumulation was studied by siRNA-mediated knockdown of all expressed members of this receptor class. The biological characteristics and function of mature adipocytes lacking selected aGPCR were analyzed by mass spectrometry and biochemical methods (lipolysis, glucose uptake, adiponectin secretion). Results More than ten aGPCR are significantly expressed in visceral and subcutaneous adipose tissues and several aGPCR are differentially regulated under high-caloric conditions in human and mouse. Receptor knockdown of six receptors resulted in an impaired adipogenesis indicating their expression is essential for proper adipogenesis. The altered lipid composition was studied in more detail for two representatives, ADGRG2/GPR64 and ADGRG6/GPR126. While GPR126 is mainly involved in adipocyte differentiation, GPR64 has an additional role in mature adipocytes by regulating metabolic processes. Conclusions Adhesion GPCR are significantly involved in qualitative and quantitative adipocyte lipid accumulation and can control lipolysis. Factors driving adipocyte formation and function are governed by signaling pathways induced by aGPCR yielding these receptors potential targets for treating obesity.

scholarly journals Targeting the 5-HT2C Receptor in Biological Context and the Current State of 5-HT2C Receptor Ligand Development

2019 ◽  
Vol 19 (16) ◽  
pp. 1381-1398 ◽  
Author(s):  
Eric A. Wold ◽  
Christopher T. Wild ◽  
Kathryn A. Cunningham ◽  
Jia Zhou
Keyword(s):  
Biological Significance ◽  
Current Status ◽  
Allosteric Modulators ◽  
Class A ◽  
Current State ◽  
The Central Nervous System ◽  
Treatment Of Obesity ◽  
And Function ◽  
Anxiety Depression ◽  
G Protein Coupled

Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of diseaserelated pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity, substance use disorders and impulse control disorders while antagonists may add value for the treatment of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDAapproved anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators (PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs are discussed in this review.

Pengembangan Instrumen Penilaian Kinerja pada Praktikum Struktur dan Fungsi Sel Di SMA Negeri 1 Kota Jambi

2016 ◽  
Vol 5 (2) ◽  
Author(s):  
Nugroho Budhiwaluyo ◽  
Rayandra Asyhar ◽  
Bambang Hariyadi
Keyword(s):  
Performance Assessment ◽  
Student Performance ◽  
Cell Structure ◽  
Structure And Function ◽  
Assessment Instrument ◽  
Product Performance ◽  
Development Model ◽  
Test Results ◽  
Validity And Reliability ◽  
And Function

  This research aims to produce a final product in the form of a performance-assessment instrument on Cell Structure and Function experiment. The development model is ADDIE. Based on expert's judgment, the instrument was valid and can be tested in the field. Field-test results shown that the product performs high validity and reliability value on measuring student performance on Cell Structure and Function experiment. Therefore, it is concluded that this performance-assessment instrument theoretically and practically has a good quality for measuring student performance in both process and product performance on Cell Structure and Function experiment. Keywords: Development, Performance-Assessment Instrument, Cell Structure and Function Experiment 

scholarly journals Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

2014 ◽  
Vol 222 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Jillian L Rourke ◽  
Shanmugam Muruganandan ◽  
Helen J Dranse ◽  
Nichole M McMullen ◽  
Christopher J Sinal
Keyword(s):  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Stromal Vascular Fraction ◽  
Tolerance Test ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Elevated Glucose ◽  
And Function ◽  
G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

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

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 ◽  
Receptor Family

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.

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