Specificity of Gβγ Signaling Depends on Gα Subunit Coupling with G-Protein-Sensitive K&lt;sup&gt;+&lt;/sup&gt; Channels

Geng, Xian; Du, Xiaona; Rusinova, Radda; Liu, Boyi; Li, Fang; Zhang, Xuan; Chen, Xing-juan; Logothetis, Diomedes E.; Zhang, Hailin

doi:10.1159/000227772

Cited by 7 publications

(6 citation statements)

References 83 publications

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“…A second study showed that different combinations of recombinant and purified Gβγ dimers directly activated GIRK channels6. Today, there is agreement that Gβγ subunits activate GIRK channels and, although there have been no further experiments demonstrating that Gα activates GIRK channels, Gαi/o G proteins are still considered important regulators of GIRK channels affecting receptor specificity and basal channel activity82,84,85,92,99,100,169.…”

Section: Discussionmentioning

confidence: 99%

“…Second, PTX-sensitive Gα subunits can associate directly with GIRK channels and alter channel gating84,85,98,99. In fact, Gα may also be involved in establishing receptor specificity such that stimulation of GPCRs that couple to only PTX-sensitive G proteins activate GIRK channels84,100. Third, spectroscopic studies with fluorescently tagged GPCRs, G proteins and regulator of G protein signaling (RGS) proteins, have provided details on the spatial relationship between proteins within this macromolecular signaling complex26,92,94,96,101,102 (see Box 2).…”

Section: A Macromolecular Signaling Complex For Girk Channelsmentioning

confidence: 99%

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Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

2010

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G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to the activation of many G-protein coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on their subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death that may be important in the pathophysiology of human diseases such as epilepsy, Down’s syndrome, Parkinson’s disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target for treating these health problems.

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Section: Discussionmentioning

confidence: 99%

Section: A Macromolecular Signaling Complex For Girk Channelsmentioning

confidence: 99%

Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

2010

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“…Many of the G proteincoupled receptor-dependent physiological processes inhibited by PTX are mediated by Gβγ subunits released from Gi/o proteins [28]. We found that inhibition of Gβγ with Gallein blocked CB2R activation-induced β-endorphin release.…”

Section: Discussionmentioning

confidence: 63%

Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release

Gao

Zhang

et al. 2015

Mol Neurobiol

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Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gβγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced β-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced β-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced β-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced β-endorphin release through Gi/o-Gβγ-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.

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“…G-protein βγ subunits activate GIRK channels through direct binding with amino- and carboxyl-ends of the channels [ 2 , 22 ]. The G-protein α subunit was not thought to be responsible for GIRK channel activation, but rather to be a regulator of the specificity of channel activation [ 4 , 23 ]. Among addictive substances, alcohol activates GIRK channels in a G-protein-independent manner [ 24 ], whereas cocaine and phencyclidine directly inhibit GIRK channels at toxic concentrations [ 25 , 26 ].…”

Section: Fundamental Function Of Girk Channels and Response To Addict...mentioning

confidence: 99%

GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

2022

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Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

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Specificity of Gβγ Signaling Depends on Gα Subunit Coupling with G-Protein-Sensitive K<sup>+</sup> Channels

Cited by 7 publications

References 83 publications

Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release

GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

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