New insights into the in vivo function of heterotrimeric G-proteins through gene deletion studies

1999 ◽  
Vol 360 (1) ◽  
pp. 5-13 ◽  
Author(s):  
Stefan Offermanns
Keyword(s):  
G Proteins ◽  
Gene Deletion ◽  
Heterotrimeric G Proteins

scholarly journals In Vivo Metabolic Roles of G Proteins of the Gi Family Studied with Novel Mouse Models

Endocrinology ◽  
2021 ◽  
Author(s):  
Jürgen Wess
Keyword(s):  
G Proteins ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Plasma Free Fatty Acid ◽  
Genetically Engineered ◽  
Whole Body ◽  
Heterotrimeric G Proteins ◽  
Structural And Functional Properties ◽  
Genetically Engineered Mice

Abstract G protein-coupled receptors (GPCRs) are the target of ~30-35% of all FDA-approved drugs. The individual members of the GPCR superfamily couple to one or more functional classes of heterotrimeric G proteins. The physiological outcome of activating a particular GPCR in vivo depends on the pattern of receptor distribution and the type of G proteins activated by the receptor. Based on the structural and functional properties of their α-subunits, heterotrimeric G proteins are subclassified into four major families: Gs, Gi/o, Gq/11, and G12/13. Recent studies with genetically engineered mice have yielded important novel insights into the metabolic roles of Gi/o-type G proteins. For example, recent data indicate that Gi signaling in pancreatic α-cells plays a key role in regulating glucagon release and whole body glucose homeostasis. Receptor-mediated activation of hepatic Gi signaling stimulates hepatic glucose production, suggesting that inhibition of hepatic Gi signaling could prove clinically useful to reduce pathologically elevated blood glucose levels. Activation of adipocyte Gi signaling reduces plasma free fatty acid levels, thus leading to improved insulin sensitivity in obese, glucose-intolerant mice. These new data suggest that Gi-coupled receptors that are enriched in metabolically important cell types represent potential targets for the development of novel drugs useful for the treatment of type 2 diabetes and related metabolic disorders.

Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs

2021 ◽  
Vol 61 (1) ◽  
pp. 421-440
Author(s):  
Lei Wang ◽  
Lu Zhu ◽  
Jaroslawna Meister ◽  
Derek B.J. Bone ◽  
Sai P. Pydi ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Membrane Receptors ◽  
Designer Drug ◽  
Heterotrimeric G Proteins ◽  
Distinct Cell Type ◽  
The Individual

G protein–coupled receptors (GPCRs) form a superfamily of plasma membrane receptors that couple to four major families of heterotrimeric G proteins, Gs, Gi, Gq, and G12. GPCRs represent excellent targets for drug therapy. Since the individual GPCRs are expressed by many different cell types, the in vivo metabolic roles of a specific GPCR expressed by a distinct cell type are not well understood. The development of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) that selectively couple to distinct classes of heterotrimeric G proteins has greatly facilitated studies in this area. This review focuses on the use of DREADD technology to explore the physiological and pathophysiological roles of distinct GPCR/G protein cascades in several metabolically important cell types. The novel insights gained from these studies should stimulate the development of GPCR-based treatments for major metabolic diseases such as type 2 diabetes and obesity.

scholarly journals Heterotrimeric G proteins physically associated with the lipopolysaccharide receptor CD14 modulate both in vivo and in vitro responses to lipopolysaccharide.

1998 ◽  
Vol 102 (11) ◽  
pp. 2019-2027 ◽  
Author(s):  
K R Solomon ◽  
E A Kurt-Jones ◽  
R A Saladino ◽  
A M Stack ◽  
I F Dunn ◽  
...  
Keyword(s):  
G Proteins ◽  
Heterotrimeric G Proteins ◽  
Lipopolysaccharide Receptor

scholarly journals Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

2021 ◽  
Author(s):  
Li-Nan Wang ◽  
Xiang-Lei Peng ◽  
Min Xu ◽  
Yuan-Bo Zheng ◽  
Yue-Ying Jiao ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Gene Deletion ◽  
Human Respiratory Syncytial Virus ◽  
Temperature Sensitive ◽  
T7 Promoter ◽  
Vaccine Candidates ◽  
Rsv Infection ◽  
Syncytial Virus

AbstractHuman respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5′ to 3′) a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed  temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.

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