RGS proteins, GRKs, and beta-arrestins modulate G protein-mediated signaling pathways in asthma

A number of diverse G-protein signaling pathways have been shown to regulate insulin secretion from pancreatic β-cells. Accordingly, regulator of G-protein signaling (RGS) proteins have also been implicated in coordinating this process. One such protein, RGS4, is reported to show both positive and negative effects on insulin secretion from β-cells depending on the physiologic context under which it was studied. We here use an RGS4-deficient mouse model to characterize previously unknown G-protein signaling pathways that are regulated by RGS4 during glucose-stimulated insulin secretion from the pancreatic islets. Our data show that loss of RGS4 results in a marked deficiency in glucose-stimulated insulin secretion during both phase I and phase II of insulin release in intact mice and isolated islets. These deficiencies are associated with lower cAMP/PKA activity and a loss of normal calcium surge (phase I) and oscillatory (phase II) kinetics behavior in the RGS4-deficient β-cells, suggesting RGS4 may be important for regulation of both Gαi and Gαq signaling control during glucose-stimulated insulin secretion. Together, these studies add to the known list of G-protein coupled signaling events that are controlled by RGS4 during glucose-stimulated insulin secretion and highlight the importance of maintaining normal levels of RGS4 function in healthy pancreatic tissues.

Download Full-text

A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

Clinical Science ◽

10.1042/cs20190579 ◽

2020 ◽

Vol 134 (5) ◽

pp. 473-512 ◽

Cited By ~ 5

Author(s):

Ryan P. Ceddia ◽

Sheila Collins

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Signaling Pathways ◽

G Protein ◽

Uncoupling Protein ◽

Beige Adipocytes ◽

Nucleotide Regulation ◽

Ucp1 Expression ◽

Thermogenic Adipocytes ◽

G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

Download Full-text

G-Protein-coupled receptor kinases, protein kinase C and beta-arrestins regulate functional desensitization of the extracellular Calcium-sensing Receptor (CaR) via distinct mechanisms

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2006-932844 ◽

2006 ◽

Vol 114 (S 1) ◽

Author(s):

S Lorenz ◽

R Frenzel ◽

S Miedlich

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

G Protein ◽

Extracellular Calcium ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

Kinase C ◽

Receptor Kinases ◽

Beta Arrestins ◽

G Protein Coupled

Download Full-text

Established and Emerging Fluorescence-Based Assays for G-Protein Function: Heterotrimeric G-Protein Alpha Subunits and Regulator of G-Protein Signaling (RGS) Proteins

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/138620703106298491 ◽

2003 ◽

Vol 6 (4) ◽

pp. 399-407 ◽

Cited By ~ 24

Author(s):

Randall Kimple ◽

Miller Jones ◽

Adam Shutes ◽

Benjamin Yerxa ◽

David Siderovski ◽

...

Keyword(s):

G Protein ◽

Protein Function ◽

G Protein Signaling ◽

Rgs Proteins ◽

Protein Signaling ◽

Heterotrimeric G Protein ◽

Alpha Subunits

Download Full-text

Rgs4 is a regulator of mTOR activity required for motoneuron axon outgrowth and neuronal development in zebrafish

Scientific Reports ◽

10.1038/s41598-021-92758-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aya Mikdache ◽

Marie-José Boueid ◽

Lorijn van der Spek ◽

Emilie Lesport ◽

Brigitte Delespierre ◽

...

Keyword(s):

Nervous System ◽

G Protein ◽

Neural Development ◽

Neuronal Development ◽

Axon Outgrowth ◽

Rgs Proteins ◽

Protein Signaling ◽

Loss Of Function ◽

G Protein Coupled

AbstractThe Regulator of G protein signaling 4 (Rgs4) is a member of the RGS proteins superfamily that modulates the activity of G-protein coupled receptors. It is mainly expressed in the nervous system and is linked to several neuronal signaling pathways; however, its role in neural development in vivo remains inconclusive. Here, we generated and characterized a rgs4 loss of function model (MZrgs4) in zebrafish. MZrgs4 embryos showed motility defects and presented reduced head and eye sizes, reflecting defective motoneurons axon outgrowth and a significant decrease in the number of neurons in the central and peripheral nervous system. Forcing the expression of Rgs4 specifically within motoneurons rescued their early defective outgrowth in MZrgs4 embryos, indicating an autonomous role for Rgs4 in motoneurons. We also analyzed the role of Akt, Erk and mechanistic target of rapamycin (mTOR) signaling cascades and showed a requirement for these pathways in motoneurons axon outgrowth and neuronal development. Drawing on pharmacological and rescue experiments in MZrgs4, we provide evidence that Rgs4 facilitates signaling mediated by Akt, Erk and mTOR in order to drive axon outgrowth in motoneurons and regulate neuronal numbers.

Download Full-text

Mice with Deficiency of G Protein γ3 Are Lean and Have Seizures

Molecular and Cellular Biology ◽

10.1128/mcb.24.17.7758-7768.2004 ◽

2004 ◽

Vol 24 (17) ◽

pp. 7758-7768 ◽

Cited By ~ 54

Author(s):

William F. Schwindinger ◽

Kathryn E. Giger ◽

Kelly S. Betz ◽

Anna M. Stauffer ◽

Elaine M. Sunderlin ◽

...

Keyword(s):

Signaling Pathways ◽

G Protein ◽

Gene Targeting ◽

Wild Type ◽

Phenotypic Changes ◽

Reduced Body ◽

Γ Subunit ◽

Body Weights ◽

The Brain ◽

Increased Susceptibility

ABSTRACT Emerging evidence suggests that the γ subunit composition of an individual G protein contributes to the specificity of the hundreds of known receptor signaling pathways. Among the twelve γ subtypes, γ3 is abundantly and widely expressed in the brain. To identify specific functions and associations for γ3, a gene-targeting approach was used to produce mice lacking the Gng3 gene (Gng3 −/−). Confirming the efficacy and specificity of gene targeting, Gng3 −/− mice show no detectable expression of the Gng3 gene, but expression of the divergently transcribed Bscl2 gene is not affected. Suggesting unique roles for γ3 in the brain, Gng3 −/− mice display increased susceptibility to seizures, reduced body weights, and decreased adiposity compared to their wild-type littermates. Predicting possible associations for γ3, these phenotypic changes are associated with significant reductions in β2 and αi3 subunit levels in certain regions of the brain. The finding that the Gng3 −/− mice and the previously reported Gng7 −/− mice display distinct phenotypes and different αβγ subunit associations supports the notion that even closely related γ subtypes, such as γ3 and γ7, perform unique functions in the context of the organism.

Download Full-text