GIRK Channel Plasticity and Implications for Drug Addiction

Velasco, Ezequiel Marrón Fernández de; McCall, Nora M.; Wickman, Kevin

doi:10.1016/bs.irn.2015.05.011

Cited by 19 publications

(7 citation statements)

References 224 publications

(319 reference statements)

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“…However, only a significant upregulation of GIRK1 was observed in the CPu after morphine and PD168,077 treatments as no expression change of GIRK2 was found. It is well established that GIRK1 requires the interaction with other GIRK subunits to reach the cell surface and therefore to form functional channels [ 35 , 78 , 79 ]. Thus, further studies will be needed to clearly characterize the subunits that form the GIRK channel heterotetramers that operates in the dorsal striatal MSNs and its function regarding the regulation of morphine effects.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

Rivera

Suárez-Boomgaard

Miguélez

et al. 2021

Cells

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Long-term exposition to morphine elicits structural and synaptic plasticity in reward-related regions of the brain, playing a critical role in addiction. However, morphine-induced neuroadaptations in the dorsal striatum have been poorly studied despite its key function in drug-related habit learning. Here, we show that prolonged treatment with morphine triggered the retraction of the dendritic arbor and the loss of dendritic spines in the dorsal striatal projection neurons (MSNs). In an attempt to extend previous findings, we also explored whether the dopamine D4 receptor (D4R) could modulate striatal morphine-induced plasticity. The combined treatment of morphine with the D4R agonist PD168,077 produced an expansion of the MSNs dendritic arbors and restored dendritic spine density. At the electrophysiological level, PD168,077 in combination with morphine altered the electrical properties of the MSNs and decreased their excitability. Finally, results from the sustantia nigra showed that PD168,077 counteracted morphine-induced upregulation of μ opioid receptors (MOR) in striatonigral projections and downregulation of G protein-gated inward rectifier K+ channels (GIRK1 and GIRK2) in dopaminergic cells. The present results highlight the key function of D4R modulating morphine-induced plasticity in the dorsal striatum. Thus, D4R could represent a valuable pharmacological target for the safety use of morphine in pain management.

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Section: Discussionmentioning

confidence: 99%

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

Rivera

Suárez-Boomgaard

Miguélez

et al. 2021

Cells

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show abstract

“…Whether this also blocks action potentials remains to be determined. In any case G-coupled signaling cascades can undergo plasticity (Han et al 2006; de Velasco, McCall, and Wickman 2015). It has also been shown that in cortical and habenular neurons, which express GIRKs, cocaine or aversive stimuli weaken the coupling to the effectors (Hearing et al 2013; Lecca et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Zessen

Flakowski

Lüscher

2021

Preprint

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Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signalling pathway decreased the number of cocaine-responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

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“…25 GIRK channels have been functionally associated with drug addiction, pain perception, and other disorders, in particular as major mediators for opioid-induced function in both central and periphery nerves system. [26][27][28] The four subunits of GIRK (GIRK1-4) function by forming various heterotetrameric and homotetrameric channels in different mammalian tissues. 29 In neurons, GIRK1/GIRK2 or GIRK1/GIRK3 hereotetramer and GIRK2/GIRK2 homotetramer are generally formed.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of GIRK2 Mediated by PPARγ Inhibition in DRG Contributes to the Neuropathic Pain Induced by Spare Nerve Injury

Mai¹,

Ji²,

Luo³

2020

Preprint

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Neuropathic pain, as the most common chronic and intractable neurological disorder, seriously endangers the health and even life of patients. Due to the unclear mechanism, there is no effective treatment for neuropathic pain at present. Here, we used spared nerve injury (SNI) rat model to investigate the underlying mechanism involved in neuropathic pain. We found that SNI significantly decreased the expression of G protein-coupled inwardly rectifying potassium channel subunit 2 (GIRK2) and peroxisome proliferation-activated receptor gamma (PPARγ) in dorsal root ganglion (DRG). Activation of GIRK2 by intrathecal injection of activators-ML-297 or overexpression of GIRK2 by intrathecal injection of adenovirus associated virus (AAVs)-AAV-GIRK2-EGFP remarkably attenuated the mechanical allodynia induced by SNI in rats. Similarly, activation or overexpression of PPARγ also relieved the SNI-induced mechanical allodynia. We further found that the expression of PPARγ was co-localized with GIRK2-positive neurons, and overexpression of PPARγ rescued the down-regulation of GIRK2 induced by SNI. The results of chromatin immunoprecipitation (ChIP) assays further showed that PPARγ was bound to the potential binding site in the promoter region of GIRK2, and overexpression of PPARγ recovered the binding in GIRK2 promoter region in DRG, which was decreased by SNI. Altogether, our results suggested that the reduction of PPARγ induced downregulation of GIRK2 in DRG, whichwas involved in SNI-induced mechanical allodynia.

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GIRK Channel Plasticity and Implications for Drug Addiction

Cited by 19 publications

References 224 publications

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Downregulation of GIRK2 Mediated by PPARγ Inhibition in DRG Contributes to the Neuropathic Pain Induced by Spare Nerve Injury

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