Addictive drugs modulate GIRK-channel signaling by regulating RGS proteins

Lomazzi, Marta; Slesinger, Paul A.; Lüscher, Christian

doi:10.1016/j.tips.2008.07.011

Cited by 36 publications

(38 citation statements)

References 47 publications

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“…For example, agonists of the μ-opioid receptor, such as enkephalins and morphine, promote Gβγ-dependent activation of GIRK channels in GABAergic neurons. The resulting disinhibition of these neurons has been shown to underlie some of the effects associated with opioid actions in vivo, including antinociception and locomotor activity (40,41). We found that R7BP −/− mice exhibited enhanced basal latency to a thermal stimulus (Fig.…”

Section: R7bp Allosterically Regulates Assembly Of R7-rgs/gβ5mentioning

confidence: 75%

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GIRK channel modulation by assembly with allosterically regulated RGS proteins

Zhou¹,

Chisari

Raehal

et al. 2012

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

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G-protein-activated inward-rectifying K + (GIRK) channels hyperpolarize neurons to inhibit synaptic transmission throughout the nervous system. By accelerating G-protein deactivation kinetics, the regulator of G-protein signaling (RGS) protein family modulates the timing of GIRK activity. Despite many investigations, whether RGS proteins modulate GIRK activity in neurons by mechanisms involving kinetic coupling, collision coupling, or macromolecular complex formation has remained unknown. Here we show that GIRK modulation occurs by channel assembly with R7-RGS/ Gβ5 complexes under allosteric control of R7 RGS-binding protein (R7BP). Elimination of R7BP occludes the Gβ5 subunit that interacts with GIRK channels. R7BP-bound R7-RGS/Gβ5 complexes and Gβγ dimers interact noncompetitively with the intracellular domain of GIRK channels to facilitate rapid activation and deactivation of GIRK currents. By disrupting this allosterically regulated assembly mechanism, R7BP ablation augments GIRK activity. This enhanced GIRK activity increases the drug effects of agonists acting at Gprotein-coupled receptors that signal via GIRK channels, as indicated by greater antinociceptive effects of GABA(B) or μ-opioid receptor agonists. These findings show that GIRK current modulation in vivo requires channel assembly with allosterically regulated RGS protein complexes, which provide a target for modulating GIRK activity in neurological disorders in which these channels have crucial roles, including pain, epilepsy, Parkinson's disease and Down syndrome. Many neurotransmitters, therapeutic agents, and drugs of abuse activate metabotropic receptors coupled to the Gi/o family of heterotrimeric G proteins. These agonists modulate neuronal excitability and synaptic transmission in part by activating G-protein-activated inward-rectifying K + channels (GIRKs or Kir3s) to hyperpolarize neurons (1). The importance of this mechanism is illustrated by the diverse phenotypes exhibited by mice lacking GIRK channel subtypes, including reduced anxiety (GIRK1) (2), hyperactivity (GIRK2) (3), propensity for seizures (GIRK2) (4), and decreased morphine-mediated analgesia (GIRK2/3) (5, 6). Conversely, augmentation of GIRK activity caused by trisomic expression of the GIRK2 gene (Kcnj6) causes cognitive impairment and other phenotypes in mouse models of Down syndrome (7-9).GIRK activity is controlled in vivo by the regulator of G protein signaling (RGS) family (10-13). Regulator of G-protein signaling (RGS) proteins accelerate rates of G-protein deactivation by acting as GTPase-activating proteins (GAPs) for Gprotein α-subunits (14-16). Thus, rapid deactivation of GIRK currents requires RGS proteins because GAP activity accelerates the rate that Gi/oα subunits hydrolyze GTP and reform inactive GDP-bound Gαβγ heterotrimers.RGS proteins have been suggested to regulate GIRK gating kinetics by several mechanisms, including kinetic coupling, collisional coupling, and macromolecular complex formation with GIRK channels. Complex formation between GIRK channels ...

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Section: R7bp Allosterically Regulates Assembly Of R7-rgs/gβ5mentioning

confidence: 75%

“…4C). Furthermore, activation of GABA(B) receptors, which also act via GIRK channels to disinhibit GABAergic neuron firing in nociceptive pathways (41), also elicited enhanced antinociception in R7BP −/− mice (Fig. 4D).…”

Section: R7bp Allosterically Regulates Assembly Of R7-rgs/gβ5mentioning

confidence: 91%

GIRK channel modulation by assembly with allosterically regulated RGS proteins

Zhou¹,

Chisari

Raehal

et al. 2012

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

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“…It is noteworthy that there were no apparent differences in the expression of D2, D3, DAT, or TH mRNA between MAM-and saline-treated rats. Given that the hyperpolarization and suppression of dopamine neuron excitability D2 receptor are mediated via the activation of GIRK2 (Kuzhikandathil et al, 1998), the coupling efficiency of which is enhanced by RGS2 protein (Lomazzi et al, 2008), we also examined the expression of these mediators of D2 receptor function. Neither GIRK2 nor RGS2 were significantly altered throughout the VTA of MAM-treated rats.…”

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confidence: 99%

Aberrant Dopamine D2-Like Receptor Function in a Rodent Model of Schizophrenia

Perez¹,

Lodge²

2012

J Pharmacol Exp Ther

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Based on the observation that antipsychotic medications display antagonist properties at dopamine D2-like receptors, aberrant dopamine signaling has been proposed to underlie psychosis in patients with schizophrenia. Thus, it is not surprising that considerable research has been devoted to understanding the mechanisms involved in the antipsychotic action of these compounds. It is important to note that the majority of these studies have been performed in "normal" experimental animals. Given that these animals do not possess the aberrant neuronal information processing typically associated with schizophrenia, the aim of the current study was to examine the dopamine D2 receptor system in a rodent model of schizophrenia. Here, we demonstrate that methylazoxymethanol acetate (MAM)-treated rats display an enhanced effect of quinpirole on dopamine neuron activity and an aberrant locomotor response to D2-like receptor activation, suggesting changes in postsynaptic D2-like receptor function. To better understand the mechanisms underlying the enhanced response to D2-like ligands in MAMtreated rats, we examined the expression of D2, D3, and dopamine transporter mRNA in the nucleus accumbens and ventral tegmental area by quantitative reverse transcriptionpolymerase chain reaction. MAM-treated rats displayed a significant increase in dopamine D3 receptor mRNA expression in the nucleus accumbens with no significant changes in the expression of the D2 receptor. Taken together, these data demonstrate robust alterations in dopamine D2-like receptor function in a rodent model of schizophrenia and provide evidence that preclinical studies examining the mechanisms of antipsychotic drug action should be performed in animal models that mirror aspects of the abnormal neuronal transmission thought to underlie symptoms of schizophrenia.

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“…Some RGS proteins are expressed in brain areas important for reward, where they could modulate GIRK channel activity (Gold, Ni, Dohlman, & Nestler, 1997). Moreover, the expression of some RGS proteins, including RGS2, RGS4, RGS6, and RGS9, is regulated by drugs of abuse (Lomazzi, Slesinger, & Luscher, 2008;Traynor, 2010). More information about the role of RGS proteins in the regulation of GPCR-GIRK signaling can be found in Chapter 3.…”

Section: Rgs Proteinsmentioning

confidence: 99%