scholarly journals Hypercholesterolemia risk associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol level in human and mouse

2020 ◽  
Author(s):  
Fangfang Han ◽  
Xiao Liu ◽  
Chuanfang Chen ◽  
Yinan Liu ◽  
Mingkun Du ◽  
...  
Keyword(s):  
Cholesterol Level ◽  
G Protein ◽  
Association Studies ◽  
Blood Cholesterol ◽  
Genome Wide Association Studies ◽  
Blood Cholesterol Level ◽  
High Fat ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Human And Mouse

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with dyslipidemia. However, about 95% of of these variants are located in genome noncoding regions and cluster in different loci. The disease-causing variant for each locus and underline mechanism remain largely unknown. We systematically analyzed these noncoding variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with increased expression of GPR146 in human and targeted activation of the rs1997243 site specifically up regulates GPR146 expression in cultured cells. GPR146 is an orphan G-protein coupled receptor that is located on plasma membrane and responses to stimulation of heat-inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in mice. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol level in both human and mouse. Our results also suggest that antagonizing GPR146 function will be an effective strategy to treat hypercholesterolemia.

scholarly journals G protein-coupled receptor kinase 5 regulates thrombin signaling in platelets via PAR-1

2021 ◽  
Author(s):  
Kate Downes ◽  
Xuefei Zhao ◽  
Nicholas S Gleadall ◽  
Harriet McKinney ◽  
Carly Kempster ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Function ◽  
Association Studies ◽  
Interindividual Variation ◽  
Genome Wide Association Studies ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Functional Responses ◽  
Glycoprotein Vi ◽  
G Protein Coupled

The interindividual variation in the functional response of platelets to activation by agonists is heritable. Genome-wide association studies (GWAS) of quantitative measures of platelet function have thus far identified fewer than 20 distinctly associated variants, some with unknown mechanisms. Here, we report GWAS of pathway specific functional responses to agonism by ADP, a glycoprotein VI-specific collagen mimetic and thrombin receptor-agonist peptides, each specific to one of the G protein-coupled receptors PAR-1 and PAR-4, in subsets of 1,562 individuals. We identified an association (P=2.75x10-40) between a common intronic variant, rs10886430 in the G protein-coupled receptor kinase 5 gene (GRK5), and the sensitivity of platelets to activate through PAR-1. The variant resides in a megakaryocyte-specific enhancer bound by the transcription factors GATA1 and MEIS1. The minor allele (G) is associated with fewer GRK5 transcripts in platelets and greater sensitivity of platelets to activate through PAR-1. We show that thrombin mediated activation of human platelets causes binding of GRK5 to PAR-1 and that deletion of the mouse homologue Grk5 enhances thrombin induced platelet activation sensitivity and increases platelet accumulation at the site of vascular injury. This corroborates evidence that the human G-allele of rs10886430 associates with greater risks of cardiovascular diseases. In summary, by combining the results of pathway specific GWAS and eQTL studies in humans with the results of platelet function studies in Grk5-/- mice, we obtain evidence that GRK5 regulates the human platelet response to thrombin via the PAR-1 pathway.

Cloning of Human and Mouse EBI1, a Lymphoid-Specific G-Protein-Coupled Receptor Encoded on Human Chromosome 17q12-q21.2

Genomics ◽  
1994 ◽  
Vol 23 (3) ◽  
pp. 643-650 ◽  
Author(s):  
Vicki L. Schweickart ◽  
Carol J. Raport ◽  
Ronald Godiska ◽  
Mary G. Byers ◽  
Roger L. Eddy ◽  
...  
Keyword(s):  
Human Chromosome ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Human And Mouse

scholarly journals Atypical cannabinoid ligands O-1602 and O-1918 administered chronically in diet-induced obesity

2019 ◽  
Vol 8 (3) ◽  
pp. 203-216 ◽  
Author(s):  
Anna C Simcocks ◽  
Kayte A Jenkin ◽  
Lannie O’Keefe ◽  
Chrishan S Samuel ◽  
Michael L Mathai ◽  
...  
Keyword(s):  
Body Weight ◽  
G Protein ◽  
High Fat Diet ◽  
Chow Diet ◽  
Sprague Dawley ◽  
High Fat ◽  
G Protein Coupled Receptor ◽  
Diet Induced Obesity ◽  
Sprague Dawley Rats ◽  
G Protein Coupled

Atypical cannabinoid compounds O-1602 and O-1918 are ligands for the putative cannabinoid receptors G protein-coupled receptor 55 and G protein-coupled receptor 18. The role of O-1602 and O-1918 in attenuating obesity and obesity-related pathologies is unknown. Therefore, we aimed to determine the role that either compound had on body weight and body composition, renal and hepatic function in diet-induced obesity. Male Sprague–Dawley rats were fed a high-fat diet (40% digestible energy from lipids) or a standard chow diet for 10 weeks. In a separate cohort, male Sprague–Dawley rats were fed a high-fat diet for 9 weeks and then injected daily with 5 mg/kg O-1602, 1 mg/kg O-1918 or vehicle (0.9% saline/0.75% Tween 80) for a further 6 weeks. Our data demonstrated that high-fat feeding upregulates whole kidney G protein receptor 55 expression. In diet-induced obesity, we also demonstrated O-1602 reduces body weight, body fat and improves albuminuria. Despite this, treatment with O-1602 resulted in gross morphological changes in the liver and kidney. Treatment with O-1918 improved albuminuria, but did not alter body weight or fat composition. In addition, treatment with O-1918 also upregulated circulation of pro-inflammatory cytokines including IL-1α, IL-2, IL-17α, IL-18 and RANTES as well as plasma AST. Thus O-1602 and O-1918 appear not to be suitable treatments for obesity and related comorbidities, due to their effects on organ morphology and pro-inflammatory signaling in obesity.

scholarly journals A hypertension patient-derived iPSC model demonstrates a role for G protein-coupled estrogen receptor in hypertension risk and development

2020 ◽  
Vol 319 (5) ◽  
pp. C825-C838 ◽  
Author(s):  
Natalie C. Fredette ◽  
Eliyah Malik ◽  
Marah L. Mukhtar ◽  
Eric R. Prossnitz ◽  
Naohiro Terada
Keyword(s):  
Endothelial Cells ◽  
Estrogen Receptor ◽  
G Protein ◽  
Vascular Endothelial Cells ◽  
Association Studies ◽  
No Production ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Increased Risk ◽  
G Protein Coupled

Hypertension (HTN) is a polyfactorial disease that can manifest severe cardiovascular pathologies such as heart failure or stroke. Genome-wide association studies (GWAS) of HTN indicate that single-nucleotide polymorphisms (SNPs) contribute to increased risk for HTN and resistance to some HTN drug regimens (Hiltunen TP et al., J Am Heart Assoc 4: e001521, 2015; Le MT et al., PLoS One 8: e52062, 2013; McDonough CW et al., J Hypertens 31: 698–704, 2013; Vandell AG et al., Hypertension 60: 957–964, 2012). However, cellular mechanistic insights of such SNPs remain largely unknown. Using a bank of induced pluripotent stem cells (iPSCs) derived from patients with HTN and CRISPR/Cas9-mediated gene-editing approach, we investigated the effects of a female HTN risk-associated SNP (rs1154431) of the G protein-coupled estrogen receptor (GPER) (Bassuk SS, Manson JE., Clin Chem 60: 68–77, 2014) in vascular endothelial cells. Although GPER1 deletion reduced endothelial nitric oxide synthase (eNOS) activation in iPSC-derived endothelial cells (iECs), the polymorphism itself did not significantly affect eNOS and NO production in a comparison of isogenic hemizygous iECs expressing either normal (P16) or HTN-associated (L16) GPER. Interestingly, we demonstrate for the first time that GPER plays a role in regulation of adhesion molecule expression and monocyte adhesion to iECs. Moreover, the L16 iECs had higher expression of inflammation genes than P16 iECs, implying that the risk variant may affect carrier individuals through increased inflammatory activity. This study further indicates that iPSCs are a useful platform for exploring mechanistic insights underlying hypertension GWAS endeavors.

scholarly journals Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice

Cell Research ◽  
2020 ◽  
Vol 30 (4) ◽  
pp. 363-365
Author(s):  
Fangfang Han ◽  
Xiao Liu ◽  
Chuanfang Chen ◽  
Yinan Liu ◽  
Mingkun Du ◽  
...  
Keyword(s):  
G Protein ◽  
Blood Cholesterol ◽  
G Protein Coupled Receptor ◽  
Cholesterol Levels ◽  
G Protein Coupled

scholarly journals A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Zhaoyang Liu ◽  
Amro A Hussien ◽  
Yunjia Wang ◽  
Terry Heckmann ◽  
Roberto Gonzalez ◽  
...  
Keyword(s):  
G Protein ◽  
Association Studies ◽  
Genetic Regulation ◽  
Biomechanical Properties ◽  
Axial Skeleton ◽  
Intervertebral Discs ◽  
G Protein Coupled Receptor ◽  
Connective Tissues ◽  
Cartilaginous Tissues ◽  
G Protein Coupled

Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) are essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

scholarly journals A comparative analysis of human and mouse islet G-protein coupled receptor expression

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Stefan Amisten ◽  
Patricio Atanes ◽  
Ross Hawkes ◽  
Inmaculada Ruz-Maldonado ◽  
Bo Liu ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
G Protein ◽  
Receptor Expression ◽  
G Protein Coupled Receptor ◽  
Mouse Islet ◽  
G Protein Coupled ◽  
Human And Mouse

scholarly journals Orphan G Protein Coupled Receptors in Affective Disorders

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 694 ◽  
Author(s):  
Lyndsay R. Watkins ◽  
Cesare Orlandi
Keyword(s):  
G Protein ◽  
Animal Studies ◽  
Association Studies ◽  
G Protein Coupled Receptors ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Pharmacological Targets ◽  
The Central Nervous System ◽  
Orphan Gpcrs ◽  
G Protein Coupled

G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.

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