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

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.

Download Full-text

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

10.1101/2021.02.22.432353 ◽

2021 ◽

Author(s):

Zhaoyang Liu ◽

Amro A. Hussien ◽

Yunjia Wang ◽

Terry Heckmann ◽

Roberto Gonzalez ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Association Studies ◽

Genetic Regulation ◽

Biomechanical Properties ◽

Intervertebral Discs ◽

Fine Tuning ◽

List Type ◽

Connective Tissues ◽

Cartilaginous Tissues

SummaryAdolescent 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 (e.g., ligaments and tendons), are essential for maintenance of spinal alignment. We show that the G-coupled protein receptor Adgrg6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine morphology. We show that Adgrg6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with an cAMP agonist was able to mirror aspects of receptor function in culture defining core pathways for regulation of these axial connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.HighlightsKnockout mice lacking Adgrg6 function in the tendons and ligaments of the spine develop perinatal-onset thoracic scoliosis.Loss of Adgrg6 function in cartilaginous tissues of the discs contribute to the incidence and severity of scoliosis.The loss of Adgrg6 function in spine tissues provide a model of construct validity for human adolescent idiopathic scoliosisFine tuning of the biomechanical properties of dense connective tissues is essential for maintaining spine alignment.

Download Full-text

Ovarian Cancer G protein-Coupled Receptor 1 Is Involved in Acid-Induced Apoptosis of Endplate Chondrocytes in Intervertebral Discs

Journal of Bone and Mineral Research ◽

10.1002/jbmr.2030 ◽

2013 ◽

Vol 29 (1) ◽

pp. 67-77 ◽

Cited By ~ 14

Author(s):

Feng-Lai Yuan ◽

Hui-Ren Wang ◽

Ming-Dong Zhao ◽

Wei Yuan ◽

Lu Cao ◽

...

Keyword(s):

Ovarian Cancer ◽

G Protein ◽

Intervertebral Discs ◽

G Protein Coupled Receptor ◽

Induced Apoptosis ◽

G Protein Coupled

Download Full-text

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

Blood Advances ◽

10.1182/bloodadvances.2021005453 ◽

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.

Download Full-text

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

10.1101/2020.01.09.901041 ◽

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.

Download Full-text