scholarly journals The Biased G-Protein-Coupled Receptor Agonism Bridges the Gap between the Insulin Receptor and the Metabolic Syndrome

2018 ◽  
Vol 19 (2) ◽  
pp. 575 ◽  
Author(s):  
Iryna Liauchonak ◽  
Fady Dawoud ◽  
Yatin Riat ◽  
Bessi Qorri ◽  
Manpreet Sambi ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Receptor ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
The Metabolic Syndrome ◽  
G Protein Coupled

scholarly journals G-protein-coupled Receptor Rhodopsin Regulates the Phosphorylation of Retinal Insulin Receptor

2007 ◽  
Vol 282 (13) ◽  
pp. 9865-9873 ◽  
Author(s):  
Ammaji Rajala ◽  
Robert E. Anderson ◽  
Jian-Xing Ma ◽  
Janis Lem ◽  
Muayyad R. Al-Ubaidi ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes

2005 ◽  
Vol 19 (11) ◽  
pp. 2760-2768 ◽  
Author(s):  
Isao Usui ◽  
Takeshi Imamura ◽  
Jennie L. Babendure ◽  
Hiroaki Satoh ◽  
Juu-Chin Lu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
G Protein ◽  
Kinase Activity ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
G Protein Coupled Receptor ◽  
Endothelin 1 ◽  
G Protein Coupled

Abstract G protein-coupled receptor kinases (GRKs) regulate seven-transmembrane receptors (7TMRs) by phosphorylating agonist-activated 7TMRs. Recently, we have reported that GRK2 can function as a negative regulator of insulin action by interfering with G protein-q/11 α-subunit (Gαq/11) signaling, causing decreased glucose transporter 4 (GLUT4) translocation. We have also reported that chronic endothelin-1 (ET-1) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and Gαq/11, and decreased insulin-stimulated glucose transport in 3T3-L1 adipocytes. In the current study, we have investigated the role of GRK2 in chronic ET-1-induced insulin resistance. Insulin-induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA. We further found that GRK2 mediates the inhibitory effects of ET-1 by two distinct mechanisms. Firstly, adenovirus-mediated overexpression of either wild-type (WT)- or kinase-deficient (KD)-GRK2 inhibited Gαq/11 signaling, including tyrosine phosphorylation of Gαq/11 and cdc42-associated phosphatidylinositol 3-kinase activity. Secondly, ET-1 treatment caused Ser/Thr phosphorylation of IRS-1 and IRS-1 protein degradation. Overexpression of KD-GRK2, but not WT-GRK2, inhibited ET-1-induced serine 612 phosphorylation of IRS-1 and restored activation of this pathway. Taken together, these results suggest that GRK2 mediates ET-1-induced insulin resistance by 1) inhibition of Gαq/11 activation, and this effect is independent of GRK2 kinase activity, and 2) GRK2 kinase activity-mediated IRS-1 serine phosphorylation and degradation.

scholarly journals Arthropod IGF, relaxin and gonadulin, putative orthologs of Drosophila insulin-like peptides 6, 7 and 8, likely originated from an ancient gene triplication

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9534 ◽  
Author(s):  
Jan A. Veenstra
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Insulin Receptor ◽  
G Protein ◽  
Insulin Like Growth Factor ◽  
G Protein Coupled Receptor ◽  
Insulin Receptor Tyrosine Kinase ◽  
Putative Orthologs ◽  
G Protein Coupled ◽  
Insulin Like Growth Factors

Background Insects have several genes coding for insulin-like peptides and they have been particularly well studied in Drosophila. Some of these hormones function as growth hormones and are produced by the fat body and the brain. These act through a typical insulin receptor tyrosine kinase. Two other Drosophila insulin-like hormones are either known or suspected to act through a G-protein coupled receptor. Although insulin-related peptides are known from other insect species, Drosophila insulin-like peptide 8, one that uses a G-protein coupled receptor, has so far only been identified from Drosophila and other flies. However, its receptor is widespread within arthropods and hence it should have orthologs. Such putative orthologs were recently identified in decapods and have been called gonadulins. Methodology In an effort to identify gonadulins in other arthropods public genome assemblies and short-read archives from insects and other arthropods were explored for the presence of genes and transcripts coding insulin-like peptides and their putative receptors. Results Gonadulins were detected in a number of arthropods. In those species for which transcriptome data from the gonads is available insect gonadulin genes are expressed in the ovaries and at least in some species also in the testes. In some insects differences in gonadulin expression in the ovary between actively reproducing and non-reproducing females differs more than 100-fold. Putative orthologs of Drosophila ilp 6 were also identified. In several non-Dipteran insects these peptides have C-terminally extensions that are alternatively spliced. The predicted peptides have been called arthropod insulin-like growth factors. In cockroaches, termites and stick insects genes coding for the arthropod insulin-like growth factors, gonadulin and relaxin, a third insulin-like peptide, are encoded by genes that are next to one another suggesting that they are the result of a local gene triplication. Such a close chromosomal association was also found for the arthropod insulin-like growth factor and gonadulin genes in spiders. Phylogenetic tree analysis of the typical insulin receptor tyrosine kinases from insects, decapods and chelicerates shows that the insulin signaling pathway evolved differently in these three groups. The G-protein coupled receptors that are related to the Drosophila ilp 8 receptor similarly show significant differences between those groups. Conclusion A local gene triplication in an early ancestor likely yielded three genes coding gonadulin, arthropod insulin-like growth factor and relaxin. Orthologs of these genes are now commonly present in arthropods and almost certainly include the Drosophila insulin-like peptides 6, 7 and 8.

Recent Advances in Development of GPR40 Modulators (FFA1/FFAR1): An Emerging Target for Type 2 Diabetes

2017 ◽  
Vol 17 (11) ◽  
pp. 947-958 ◽  
Author(s):  
Nutan Sharma ◽  
Sunita Bhagat ◽  
Tejpal Singh Chundawat
Keyword(s):  
G Protein ◽  
Type Ii Diabetes ◽  
Metabolic Diseases ◽  
Type Ii ◽  
G Protein Coupled Receptor ◽  
Novel Treatments ◽  
The Metabolic Syndrome ◽  
Recent Advances ◽  
Novel Drug ◽  
G Protein Coupled

Background: GPR40, an orphan G-protein coupled receptor that is activated by medium and long-chain fatty acids and is highly expressed in pancreatic islets, adipose depots and the gastrointestinal tract are involved in energy source recognition, absorption, storage and/or metabolism. Since its deorphanization in 2003, G-protein-coupled receptor GPR40 has emerged as a potential target for type II diabetes because it has been hypothesized to participate in the adverse effects of chronic fatty acid exposure on function of β-cell. </p> <p> Results: This signifies that G-protein-coupled receptors have recently emerged as novel therapeutic targets in metabolic diseases, such as diabetes, obesity and the metabolic syndrome. Therefore it seems natural that GPR40 represents a potentially attractive target to best meet the need for novel treatments for Type II diabetes. </p> <p> Conclusion: This review describes recent advances and novel drug discovery approaches in the antidiabetic area, focusing on GPR40 modulators which have been synthesized till date and their Structure-Activity Relationship (SAR).

scholarly journals Arthropod IGF, Relaxin and Gonadulin, putative orthologs of Drosophila insulin-like peptides 6, 7 and 8, likely originated from an ancient gene triplication

2020 ◽  
Author(s):  
Jan A. Veenstra
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Insulin Receptor ◽  
G Protein ◽  
Insulin Like Growth Factor ◽  
G Protein Coupled Receptor ◽  
Insulin Receptor Tyrosine Kinase ◽  
Putative Orthologs ◽  
G Protein Coupled ◽  
Insulin Like Growth Factors

AbstractBackgroundInsects have several genes coding for insulin-like peptides and they have been particularly well studied in Drosophila. Some of these hormones function as growth hormones and are produced by the fat body and the brain. These act through a typical insulin receptor tyrosine kinase. Two other Drosophila insulin-like hormones are either known or suspected to act through a G-protein coupled receptor. Although insulin-related peptides are known from other insect species, Drosophila insulin-like peptide 8, one that uses a G-protein coupled receptor, has so far only been identified from Drosophila and other flies. However, its receptor is widespread within arthropods and hence it should have orthologs. Such putative orthologs were recently identified in decapods and have been called gonadulins.MethodologyIn an effort to identify gonadulins in other arthropods public genome assemblies and short-read archives from insects and other arthropods were explored for the presence of genes and transcripts coding insulin-like peptides and their putative receptors.ResultsGonadulins were detected in a number of arthropods. In those species for which transcriptome data from the gonads is available insect gonadulin genes are expressed in the ovaries and at least in some species also in the testes. In some insects differences in gonadulin expression in the ovary between actively reproducing and non-reproducing females differs more than 100-fold. Putative orthologs of Drosophila ilp 6 were also identified. In several non-Dipteran insects these peptides have C-terminally extensions that are alternatively spliced. The predicted peptides have been called arthropod insulin-like growth factors. In cockroaches, termites and stick insects genes coding for the arthropod insulin-like growth factors, gonadulin and relaxin, a third insulin-like peptide, are encoded by genes that are next to one another suggesting that they are the result of a local gene triplication. Such a close chromosomal association was also found for the arthropod insulin-like growth factor and gonadulin genes in spiders. Phylogenetic tree analysis of the typical insulin receptor tyrosine kinases from insects, decapods and chelicerates shows that the insulin signaling pathway evolved differently in these three groups. The G-protein coupled receptors that are related to the Drosophila ilp 8 receptor similarly show significant differences between those groups.ConclusionA local gene triplication in an early ancestor likely yielded three genes coding gonadulin, arthropod insulin-like growth factor and relaxin. Orthologs of these genes are now commonly present in arthropods and almost certainly include the Drosophila insulin-like peptides 6, 7 and 8.

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