Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

Fu, Qin; Shi, Qian; West, Toni M.; Xiang, Yang

doi:10.1097/fjc.0000000000000481

Cited by 20 publications

(13 citation statements)

References 163 publications

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“…Interactions with PIP 2 are known for other membrane signaling proteins, e.g., ion channels (Hansen, 2015), receptor tyrosine kinases (Hedger et al, 2015), and neurotransmitter transporters (Khelashvili et al, 2015). Thus, our studies raise the possibility of PIP 2 -mediated crosstalk between GPCRs and other signaling systems (Fu et al, 2017) in cell membranes. Lipid interplay was revealed by the use of complex multi-component lipid bilayers, emphasizing the importance of membrane composition on modulatory effects on receptors.…”

Section: Discussionmentioning

confidence: 58%

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

et al. 2019

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Graphical Abstract Highlights d MD simulations show state-dependent binding of lipids to the Adenosine A2a receptor d Nine lipid interaction sites were revealed, for GM3, cholesterol and PIP 2 d Binding of PIP 2 enhanced the association of mini-Gs with the A2a receptor d These results indicate lipids may allosterically regulate GPCRs SUMMARY Membranes are known to have modulatory effects on G protein-coupled receptors (GPCRs) via specific lipid interactions. However, the mechanisms of such modulations in physiological conditions and how they influence GPCR functions remain unclear.Here we report coarse-grained molecular dynamics simulations on the Adenosine A2a receptor in different conformational states embedded in an in vivo-mimetic membrane model. Nine lipid interaction sites were revealed. The strength of lipid interactions with these sites showed a degree of dependence on the conformational states of the receptor, suggesting that these lipids may regulate the conformational dynamics of the receptor. In particular, we revealed a dual role of PIP 2 on A2aR activation that involves both stabilization of the characteristic outward tilt of TM6 and enhancement of A2aR-mini-Gs association. Our results demonstrated that the bound lipids allosterically regulate the functional properties of GPCRs. These protein-lipid interactions provide a springboard for design of allosteric modulators of GPCRs. which are governed by both the protein receptor and its bound lipids. This opens up new prospects for the pharmacology of GPCRs as their druggable space is expanded to include the bound lipids. The sensitivity of protein-lipid interactions toward the receptor conformational state and the lipid environment may thus provide a platform for designing subtype-selective and cell type-selective drugs. STAR+METHODSDetailed methods are provided in the online version of this paper and include the following:

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Section: Discussionmentioning

confidence: 58%

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

et al. 2019

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“…Some ligands can differentially activate a GPCR via a phenomenon known as functional selectivity or biased signaling (Wisler et al, 2014; Zweemer et al, 2014). For example, stimulation of β 2 adrenergic receptor (β 2 AR), a prototypical GPCR involved in memory and learning in the central nervous system (CNS) and regulation of metabolism and cardiovascular function, promotes phosphorylation by both GRKs and PKA (Najafi et al, 2016; Mammarella et al, 2016; Fu et al, 2017; Matera et al, 2018). We have recently identified spatially segregated subpopulations of β 2 AR undergoing exclusive phosphorylation by GRKs or PKA in a single cell.…”

Section: Introductionmentioning

confidence: 99%

β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons

Shen

Chen

Kaur

et al. 2019

eLife

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G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in mammalian cells. Here, we report neuronal excitability of β-blockers carvedilol and alprenolol at clinically relevant nanomolar concentrations. Carvedilol and alprenolol activate β2AR, which promote G protein signaling and cAMP/PKA activities without action of G protein receptor kinases (GRKs). The cAMP/PKA activities are restricted within the immediate vicinity of activated β2AR, leading to selectively enhance PKA-dependent phosphorylation and stimulation of endogenous L-type calcium channel (LTCC) but not AMPA receptor in rat hippocampal neurons. Moreover, we have engineered a mutant β2AR that lacks the catecholamine binding pocket. This mutant is preferentially activated by carvedilol but not the orthosteric agonist isoproterenol. Carvedilol activates the mutant β2AR in mouse hippocampal neurons augmenting LTCC activity through cAMP/PKA signaling. Together, our study identifies a mechanism by which β-blocker-dependent activation of GPCRs promotes spatially restricted cAMP/PKA signaling to selectively target membrane downstream effectors such as LTCC in neurons.

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“…15 The regulation of glucose metabolism is coordinated by IR and β 2 AR, which represents receptor tyrosine kinase (RTK) and G protein-coupled receptor (GPCR) signaling pathways that interact under certain pathophysiological circumstances. 16,17 The protein complex consisting of IR and β 2 AR has been characterized in the heart and the interaction between these two proteins has been demonstrated by bioluminescence resonance energy transfer (BRET) experiment. 16,18 Long-term overstimulation of βAR induces a state of insulin resistance leading to heart failure.…”

Section: Introductionmentioning

confidence: 99%

<p>Sustained Stimulation of β<sub>2</sub>AR Inhibits Insulin Signaling in H9C2 Cardiomyoblast Cells Through the PKA-Dependent Signaling Pathway</p>

Pei¹,

Xiao²,

Guo³

et al. 2020

DMSO

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Introduction: This study aimed to investigate the role of β 2 adrenergic receptor (β 2 AR) in insulin signaling transduction in H9C2 cardiomyoblast cells to understand the formation of the β 2 AR-insulin receptor (IR) protein complex and its role in insulin-induced Glut4 expression. Methods: H9C2 cells were treated with various protein inhibitors (CGP, β 1 AR inhibitor CGP20712; ICI, β 2 AR inhibitor ICI 118,551; PKI, PKA inhibitor myristoylated PKI; PD 0325901, MEK inhibitor; SP600125, JNK inhibitor) with or without insulin or isoproterenol (ISO) before RNA-sequencing (RNA-Seq) and quantitative-PCR (Q-PCR). Yeast twohybrid, co-immunoprecipitation and His-tag pull-down assay were carried out to investigate the formation of the β 2 AR-IR protein complex. The intracellular concentrations of cAMP in H9C2 cells were tested by high performance liquid chromatography (HPLC) and the phosphorylation of JNK was tested by Western blot. Results: Gene Ontology (GO) analysis revealed that the most significantly enriched processes in the domain of molecular function (MF) were catalytic activity and binding, whereas in the domain of biological processes (BP) were metabolic process and cellular process. Furthermore, the enriched processes in the domain of cellular components (CC) were cell and cell parts. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that the most significant pathways that have been altered included the PI3K-Akt and MAPK signaling pathways. Q-PCR, which was performed to verify the gene expression levels exhibited consistent results. In evaluating the signaling pathways, the sustained stimulation of β 2 AR by ISO inhibited insulin signalling, and the effect was primarily through the cAMP-PKA-JNK pathway and MEK/JNK signaling pathway. Yeast two-hybrid, coimmunoprecipitation and His-tag pull-down assay revealed that β 2 AR, IR, insulin receptor substrate 1 (IRS1), Grb2-associated binding protein 1 (GAB1) and Grb2 existed in the same protein complex. Conclusion: The sustained stimulation of β 2 AR might inhibit insulin signaling transduction through the cAMP-PKA-JNK and MEK/JNK pathways in H9C2 cells.

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Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

Cited by 20 publications

References 163 publications

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

State-dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

β-blockers augment L-type Ca2+ channel activity by targeting spatially restricted β2AR signaling in neurons

<p>Sustained Stimulation of β<sub>2</sub>AR Inhibits Insulin Signaling in H9C2 Cardiomyoblast Cells Through the PKA-Dependent Signaling Pathway</p>

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