The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor

RGS12 在 G 蛋白与 kappa 阿片受体下游 β-arrestin 信号传导的差异调节中的作用

基本信息

项目摘要

The kappa opioid receptor (KOR) helps mediate responses to stress, yet is also implicated in developing and/or maintaining health disorders of chronic pain, drug addiction, anxiety and depression. KOR agonists have shown promise in ameliorating these disorders, but are limited by dysphoric side effects. Beneficial effects of KOR agonists (e.g., analgesia) are considered predominantly mediated by G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria). However, the mechanism(s) by which these signals downstream of KOR are regulated are still being elucidated. The Regulators of G protein Signaling are intracellular proteins that accelerate signal termination after G protein-coupled receptor activation. RGS12 is a complex member of this protein family, with at least five different domains that interact with components of both G protein-dependent and -independent signaling pathways. We recently reported that RGS12 is enriched in the ventral striatum (vSTR), and global Rgs12 ablation decreases locomotor responses to dopamine (DA)-modulating psychostimulants. Our data correlate with the augmented DA transporter (DAT) expression and function in the vSTR, but not dorsal striatum (dSTR), seen in RGS12-null mice. Loss of RGS12 (especially as a Gai/o-directed GTPase-accelerating protein) may indirectly increase DAT expression / function by removing negative regulation downstream of KOR, given that KOR agonists are known to increase DAT surface expression and uptake function. Supporting this notion, the augmented DAT function and reduced AMPH-stimulated locomotion caused by RGS12 loss are both reversed following KOR antagonism. We also found elevated KOR expression in the vSTR, but not dSTR, of RGS12-null and β-arrestin2-null mouse strains. RGS12 over-expression augments β-arrestin recruitment to activated KOR – an effect preserved following pertussis toxin-mediated Gi/o inhibition or mutation to the Ga-interacting domains of RGS12, suggesting a G protein-independent mechanism. These findings are consistent with our newest data that RGS12-null mice exhibit attenuated KOR agonist-induced conditioned place aversion, considered β-arrestin-dependent behavior. Collectively, our data highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation, a regulation that may be exploitable pharmacologically to help shift KOR-mediated signaling to beneficial outcomes and away from detrimental ones. Our first aim is to determine the specific neuronal populations within which RGS12 acts to modulate G protein- dependent and -independent KOR signaling, testing hypotheses that RGS12 operates to modulate KOR and DAT function specifically in KOR- and DAT- expressing CNS neurons, and also operates at the level of the spinal cord. Our second aim is to delineate the molecular determinants that engender selective functional interactions between RGS12 and KOR. Success in pursuit of these two aims will provide key pre-clinical data for considering RGS12 a valid target for future analgesic and anti-addiction therapeutics that engage KOR signal transduction.
kappa阿片受体(kappa opioid receptor, KOR)帮助调节应激反应,但也参与发育和/或应激反应

项目成果

期刊论文数量(0)
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David P. Siderovski其他文献

PINK1 knockout rats show premotor cognitive deficits measured through a complex maze
PINK1 基因敲除大鼠显示出通过复杂迷宫测量的运动前认知缺陷
  • DOI:
    10.1101/2024.01.18.576285
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Isabel Soto;V. Nejtek;David P. Siderovski;Michael F Salvatore
  • 通讯作者:
    Michael F Salvatore
Regulators of G-Protein signalling as new central nervous system drug targets
作为新的中枢神经系统药物靶点的 G 蛋白信号调节剂
  • DOI:
    10.1038/nrd747
  • 发表时间:
    2002-03-01
  • 期刊:
  • 影响因子:
    101.800
  • 作者:
    Richard R. Neubig;David P. Siderovski
  • 通讯作者:
    David P. Siderovski
RETRACTION: A Structural Basis for Nucleotide Exchange on G-alpha-i Subunits and Receptor Coupling Specificity
收缩:G-α-i 亚基上核苷酸交换和受体偶联特异性的结构基础
  • DOI:
  • 发表时间:
    2007
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C. A. Johnston;David P. Siderovski
  • 通讯作者:
    David P. Siderovski
The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB<sub>2</sub> receptor activation
  • DOI:
    10.1016/j.neuropharm.2024.110216
  • 发表时间:
    2025-02-15
  • 期刊:
  • 影响因子:
  • 作者:
    Antonio Matt Reck;David P. Siderovski;Steven G. Kinsey
  • 通讯作者:
    Steven G. Kinsey

David P. Siderovski的其他文献

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{{ truncateString('David P. Siderovski', 18)}}的其他基金

The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor
RGS12 在 G 蛋白与 kappa 阿片受体下游 β-arrestin 信号传导的差异调节中的作用
  • 批准号:
    10348646
  • 财政年份:
    2021
  • 资助金额:
    $ 35.97万
  • 项目类别:
The role of RGS12 in differential modulation of G protein versus beta-arrestin signaling downstream of the kappa opioid receptor
RGS12 在 G 蛋白与 kappa 阿片受体下游 β-arrestin 信号传导的差异调节中的作用
  • 批准号:
    9886591
  • 财政年份:
    2021
  • 资助金额:
    $ 35.97万
  • 项目类别:
Enzymatic Screen for RGS Protein Modulators
RGS 蛋白调节剂的酶法筛选
  • 批准号:
    8066323
  • 财政年份:
    2010
  • 资助金额:
    $ 35.97万
  • 项目类别:
Enzymatic Screen for RGS Protein Modulators
RGS 蛋白调节剂的酶法筛选
  • 批准号:
    7928424
  • 财政年份:
    2010
  • 资助金额:
    $ 35.97万
  • 项目类别:
Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
异源三聚体 G 蛋白核苷酸循环的结构决定因素
  • 批准号:
    8126583
  • 财政年份:
    2010
  • 资助金额:
    $ 35.97万
  • 项目类别:
Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
异源三聚体 G 蛋白核苷酸循环的结构决定因素
  • 批准号:
    7658332
  • 财政年份:
    2008
  • 资助金额:
    $ 35.97万
  • 项目类别:
Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
异源三聚体 G 蛋白核苷酸循环的结构决定因素
  • 批准号:
    7523807
  • 财政年份:
    2008
  • 资助金额:
    $ 35.97万
  • 项目类别:
Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
异源三聚体 G 蛋白核苷酸循环的结构决定因素
  • 批准号:
    7904748
  • 财政年份:
    2008
  • 资助金额:
    $ 35.97万
  • 项目类别:
Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
异源三聚体 G 蛋白核苷酸循环的结构决定因素
  • 批准号:
    8113246
  • 财政年份:
    2008
  • 资助金额:
    $ 35.97万
  • 项目类别:
Mechanistic studies of a novel G-alpha nucleotide cycle
新型G-α核苷酸循环的机制研究
  • 批准号:
    7646459
  • 财政年份:
    2006
  • 资助金额:
    $ 35.97万
  • 项目类别:
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