Interaction of G-Protein βγ Complex with Chromatin Modulates GPCR-Dependent Gene Regulation

Bhatnagar, Anushree; Ünal, Hamiyet; Jagannathan, Rajaganapathi; Kaveti, Suma; Duan, Zhong Hui; Yong, S. L.; Vasanji, Amit; Kinter, Michael; Desnoyer, Russell; Karnik, Sadashiva S.

doi:10.1371/journal.pone.0052689

Cited by 16 publications

(12 citation statements)

References 45 publications

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“…3E, DMI treatment promotes the formation of complexes between GRK2 and Gβ subunits in the Rgs9KO group. GPCR activation also promotes complexes between Gβ subunits and the epigenetic modifier HDAC5 (22,23). HDAC5 is expressed in several brain regions, mediating sensory and affective responses and TCA actions (10,24).…”

Section: Resultsmentioning

confidence: 99%

“…3F). HDAC5 can be found in both cytoplasmic and nuclear compartments, and the nuclear translocation of this protein is controlled by phosphorylation (25,26), as well as by complexes with Gβγ subunits (22,23). Because DMI promotes complexes between Gβ subunits and HDAC5, we hypothesized that upon DMI administration, HDAC5 translocates to the nucleus and binds to chromatin complexes to suppress gene expression (an effect that delays the onset of drug action).…”

Section: Resultsmentioning

confidence: 99%

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RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…AT1R coupled to Gi/o inhibits adenylyl cyclase and some Ca++ channels and activates Rho kinase (Toth, Turu, Hunyady, & Balla, 2018). The Gβ2 subunit of the G protein interacted with specific nucleosome core histones and sequence motif of several transcription factors (Bhatnagar et al, 2013). G12 and G13 proteins activation by AT1R interact with multiple partners, including HSP90 (heat shock protein 90), AKAP (A-kinase-anchoring proteins), non-receptor tyrosine kinases, ras-GAP (GTPase-activating protein) cadherin, and Rho-GEFs.…”

Section: Angiotensin Type 1 Receptor and Blood Pressurementioning

confidence: 99%

Effect of novel GPCR ligands on blood pressure and vascular homeostasis

Jara

Singh

Ünal

et al. 2019

Methods in Cell Biology

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Maintenance of normal blood pressure under conditions of drug treatment is a measure of system-wide neuro-hormonal controls and electrolyte/fluid volume homeostasis in the body. With increased interest in designing and evaluating novel drugs that may functionally select or allosterically modulate specific GPCR signaling pathways, techniques that allow us to measure acute and long-term effects on blood pressure are very important. Therefore, this chapter describes techniques to measure acute and long-term impact of novel GPCR ligands on blood pressure regulation. We will use the angiotensin type 1 receptor, a powerful blood pressure regulating GPCR, in detailing the methodology. Normal blood pressure maintenance depends upon dynamic modulation of angiotensin type 1 receptor activity by the hormone peptide angiotensin II. Chronic activation of angiotensin type 1 receptor creates hypertension and related cardiovascular disease states which are treated with angiotensin type 1 receptor blockers (ARBs). Thus, a prototype for evaluation of blood pressure control under experimental evaluation of novel drugs.

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“…It is still unclear if cytoplasmic Gβγ sequesters HDAC or if the interaction happens in the nucleus, and whether this regulation occurs in myocytes, but these findings suggest a role for Gβγ in fine-tuning the activity of HDAC5 and MEF2C in the heart. Activation of GPCRs also promotes Gβ 2 translocation into nucleus and nuclear interaction between Gβ 2 and specific nucleosome core histones and transcriptional modulators [71]. Gβ 2 can interact with multiple transcription factors via the conserved motif (-LLTPPG-), and Gβ 2 -dependent regulation of ~2% genes in HEK-293 cells points towards a broader role of Gβ 2 in the epigenetic regulation of gene expression programs in response to GPCR activation [71].…”

Section: Targeting Of Functional Gα and Gβγ To Distinct Subcellulamentioning

confidence: 99%

“…Activation of GPCRs also promotes Gβ 2 translocation into nucleus and nuclear interaction between Gβ 2 and specific nucleosome core histones and transcriptional modulators [71]. Gβ 2 can interact with multiple transcription factors via the conserved motif (-LLTPPG-), and Gβ 2 -dependent regulation of ~2% genes in HEK-293 cells points towards a broader role of Gβ 2 in the epigenetic regulation of gene expression programs in response to GPCR activation [71]. Gα subunits can also be localized in the nucleus and interact with nuclear proteins.…”

Section: Targeting Of Functional Gα and Gβγ To Distinct Subcellulamentioning

confidence: 99%

Heterotrimeric G protein-mediated signaling and its non-canonical regulation in the heart

2015

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Heterotrimeric guanine nucleotide-binding proteins (G proteins) regulate a multitude of signaling pathways in mammalian cells by transducing signals from G protein-coupled receptors (GPCRs) to effectors, which in turn regulate cellular function. In the myocardium, G protein signaling occurs in all cardiac cell types and is centrally involved in the regulation of heart rate, pump function, and vascular tone and in the response to hemodynamic stress and injury. Perturbations in G protein-mediated signaling are well known to contribute to cardiac hypertrophy, failure and arrhythmias. Most of the currently used drugs for cardiac and other diseases target GPCR signaling. In the canonical G protein signaling paradigm, G proteins that are located at the cytoplasmic surface of the plasma membrane become activated after an agonist-induced conformational change of GPCRs, which then allows GTP-bound Gα and free Gβγ subunits to activate or inhibit effector proteins. Research over the past two decades has markedly broadened the original paradigm with a GPCR–G protein-effector at the cell surface at its core by revealing novel binding partners and additional subcellular localizations for heterotrimeric G proteins that facilitate many previously unrecognized functional effects. In this review, we focus on non-canonical and epigenetic-related mechanisms that regulate heterotrimeric G protein expression, activation and localization and discuss functional consequences using cardiac examples where possible. Mechanisms reviewed involve microRNAs, histone deacetylases, chaperones, alternative modes of G protein activation, and posttranslational modifications. Some of these newly characterized mechanisms may be further developed into novel strategies for the treatment of cardiac disease and beyond.

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Interaction of G-Protein βγ Complex with Chromatin Modulates GPCR-Dependent Gene Regulation

Cited by 16 publications

References 45 publications

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Effect of novel GPCR ligands on blood pressure and vascular homeostasis

Heterotrimeric G protein-mediated signaling and its non-canonical regulation in the heart

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