G protein-coupled receptor kinases as regulators of dopamine receptor functions

Gurevich, Eugenia V.; Gainetdinov, Raul R.; Gurevich, Vsevolod V.

doi:10.1016/j.phrs.2016.05.010

“…In mammals, GRK2 has been connected to the regulation of D2-type dopamine receptors, but the reported results are based mainly on effects of GRK2 overexpression in heterologous expression systems [55][56][57][58][59]. The results reported here provide a direct connection between GRK-2 and D2-type receptor signaling in a behaviorally relevant in vivo system.…”

Section: Introductionmentioning

confidence: 79%

“…Mammalian GRK2 and GRK3 (the orthologs of GRK-2) have been connected to the desensitization, internalization, and recycling of D2-type dopamine receptors [55][56][57][58][59]100]. Interestingly, some of the effects of GRK2 on D2 receptor function may be independent of receptor phosphorylation [57,58,100], though one caveat of these studies is that they involve GRK2 overexpression in heterologous cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our structure-function approach indicates that GPCR phosphorylation is important for GRK-2 function in locomotion and G q signaling in C. elegans, although we cannot exclude the possibility that phosphorylation of additional substrates may also be required. In vivo studies of the role of mammalian GRKs in the regulation of dopamine receptors have focused on the analysis of behaviors that are induced by psychostimulatory drugs such as cocaine that elevate the extracellular concentration of dopamine [59]. Mice with a cell-specific knockout of GRK2 in D2 receptor-expressing neurons have altered spontaneous locomotion and sensitivity to cocaine [101], though the cellular mechanisms underlying these behavioral effects are not known.…”

Section: Discussionmentioning

confidence: 99%

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Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

Topalidou

¹

,

Cooper

²

,

Pereira

³

et al. 2016

Preprint

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The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein G q and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the G q -Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit G o signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. Author summaryDopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematode C. elegans that involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a G protein-coupled receptor kinase (GRK-2) that inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this PLOS Genetics | https://doi.org/10.1371/journal.pgen

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“…In mammals, GRK2 has been connected to the regulation of D2-type dopamine receptors, but the reported results are based mainly on effects of GRK2 overexpression in heterologous expression systems [55–59]. The results reported here provide a direct connection between GRK-2 and D2-type receptor signaling in a behaviorally relevant in vivo system.…”

Section: Introductionmentioning

confidence: 82%

Dopamine negatively modulates the NCA ion channels in C. elegans

Topalidou

¹

,

Cooper

²

,

Pereira

³

et al. 2017

View full text Add to dashboard Cite

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

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“…This is because maximal binding of barr occurs at GRKphosphorylated and agonist-occupied GPCRs (19,20). The five non-visual GRKs that act on GPCRs rely on distinct plasma membrane recruitment mechanisms (21).…”

Section: Introductionmentioning

confidence: 99%

The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation

Pack

¹

,

Orlen

²

,

Ray

³

et al. 2018

Journal of Biological Chemistry

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The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and b-arrestins (barrs). Selectively engaging either the G protein or barr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to barr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates barr recruitment, bridge these pathways. Therefore barr recruitment appears to be intimately tied to G protein activation via GRKs. Here, we sought to understand how GRK2 action at the D2R would be disrupted when G protein activation is eliminated and the effect of this on barr recruitment. We used two recently developed biased D2R mutants that can preferentially interact either with G proteins or barrs as well as a barr-biased D2R ligand, UNC9994. With these functionally selective tools, we investigated the mechanism whereby the barr-preferring D2R achieves barr pathway activation in the complete absence of G protein activation. We describe how direct, G protein-independent recruitment of GRK2 drives interactions at the barr-preferring D2R and also contributes to barr recruitment at the WT D2R. Additionally, we found an additive interaction between the barr-preferring D2R mutant and UNC9994. These results reveal that the D2R can directly recruit GRK2 without G protein activation and that this mechanism may have relevance to achieving barr-biased signaling.

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G protein-coupled receptor kinases as regulators of dopamine receptor functions

Cited by 110 publications

References 208 publications

Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

Dopamine Negatively Modulates the NCA Ion Channels inC. elegans

Dopamine negatively modulates the NCA ion channels in C. elegans

The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation

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