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G 13 proteins are required for GABA B receptor-induced JNK phosphorylation. (A) Western blotting analysis of JNK phosphorylation in CGNs with G 13 siRNA and baclofen stimulation (100 M, 10 min). Blots are representative of six independent experiments. (B and C) Western blotting analysis of JNK and ERK1/2 phosphorylation in response to baclofen for the indicated time in wild-type (WT) MEFs and G 12/13 -deficient MEFs overexpressing GABA B receptor. Blots are representative of eight independent experiments. In (A) to (C), data are means ± SEM analyzed with one-way ordinary ANOVA followed by Sidak's multiple comparisons post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus basal levels; ###P < 0.001 versus treatment with the baclofen treated group; ns, nonsignificant versus G 13 siRNA basal level.
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G protein–coupled receptors (GPCRs) activate various mitogen-activated protein kinase (MAPK) pathways to regulate critical cell functions. β-Arrestins mediate this mechanism for most GPCRs but not the GABAB receptor (GABABR). When coupled to the G protein Gi/o, GABABR phosphorylates the kinases ERK1 and ERK2. Here, we uncovered a distinct β-arresti...
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... GABA B receptor by baclofen alone was not capable to increase cAMP levels in CGNs, which suggested the GABA B receptor cannot activate the G s pathway (28). Moreover, baclofen did not induce Ca 2+ signals in CGNs, in contrast to glutamate used as a positive control, indicating that the GABA B receptor cannot activate the G q type of G proteins ( fig. S2A). . Data are means ± SEM analyzed with one-way ordinary ANOVA followed by Sidak's multiple comparisons post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001 versus basal levels with no drug treatment (C to E); ##P < 0.01, ###P < 0.001; ns, nonsignificant versus treatment with the baclofen-treated group (D and ...
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... 13 in GABA B receptor-mediated JNK activation. First, we used the G 13 RNA interference (RNAi) [G 13 small interfering RNA (siRNA)] to decrease the expression of G 13 in CGNs. Our results showed that reduction in G 13 expression abolished the baclofen-induced JNK phosphorylation but had no effect on baclofen-activated ERK1/2 phosphorylation ( Fig. 2A). Then, we applied the synthetic carboxyl terminal peptide of G 13 (G 13 -CT) combined with TAT peptide, which makes the peptide permeable into CGNs. The G 13 -CT is reported to inhibit G 13 downstream signaling transduction (41,42). Our data showed that the incubation with G 13 -CT peptide inhibited baclofen-stimulated JNK ...
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... we applied the synthetic carboxyl terminal peptide of G 13 (G 13 -CT) combined with TAT peptide, which makes the peptide permeable into CGNs. The G 13 -CT is reported to inhibit G 13 downstream signaling transduction (41,42). Our data showed that the incubation with G 13 -CT peptide inhibited baclofen-stimulated JNK phosphorylation in CGNs ( fig. S2B). Similarly, in HEK293 cells expressing GABA B receptor, we knocked down G 13 using siRNA ( fig. S2C) and, separately, cotransfected cells with G 13 -CT cDNA ( fig. S2D). The results showed that GABA B receptoractivated JNK phosphorylation was blocked upon inhibition of G 13 activity. Next, we used wild-type (WT) MEFs and G 12/13 ...
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... makes the peptide permeable into CGNs. The G 13 -CT is reported to inhibit G 13 downstream signaling transduction (41,42). Our data showed that the incubation with G 13 -CT peptide inhibited baclofen-stimulated JNK phosphorylation in CGNs ( fig. S2B). Similarly, in HEK293 cells expressing GABA B receptor, we knocked down G 13 using siRNA ( fig. S2C) and, separately, cotransfected cells with G 13 -CT cDNA ( fig. S2D). The results showed that GABA B receptoractivated JNK phosphorylation was blocked upon inhibition of G 13 activity. Next, we used wild-type (WT) MEFs and G 12/13 -deficient MEFs transfected with the GABA B receptor to further confirm the effect of G 13 . Our data ...
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... inhibit G 13 downstream signaling transduction (41,42). Our data showed that the incubation with G 13 -CT peptide inhibited baclofen-stimulated JNK phosphorylation in CGNs ( fig. S2B). Similarly, in HEK293 cells expressing GABA B receptor, we knocked down G 13 using siRNA ( fig. S2C) and, separately, cotransfected cells with G 13 -CT cDNA ( fig. S2D). The results showed that GABA B receptoractivated JNK phosphorylation was blocked upon inhibition of G 13 activity. Next, we used wild-type (WT) MEFs and G 12/13 -deficient MEFs transfected with the GABA B receptor to further confirm the effect of G 13 . Our data showed that baclofen stimulation could induce JNK phosphorylation in ...
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... (WT) MEFs and G 12/13 -deficient MEFs transfected with the GABA B receptor to further confirm the effect of G 13 . Our data showed that baclofen stimulation could induce JNK phosphorylation in WT MEFs expressing the GABA B receptor (GB1 + GB2), but no activation of JNK was observed in G 12/13 -deficient MEFs expressing the GABA B receptor (Fig. 2B). Furthermore, overexpression of G 13 in G 12/13 -deficient cells expressing the GABA B receptor showed the recovery of JNK activation mediated by the GABA B receptor (Fig. 2C). Whereas ERK1/2 activation induced by baclofen was not changed in WT MEFs, G 12/13 -deficient cells expressing the GABA B receptor cotransfected without or ...
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... phosphorylation in WT MEFs expressing the GABA B receptor (GB1 + GB2), but no activation of JNK was observed in G 12/13 -deficient MEFs expressing the GABA B receptor (Fig. 2B). Furthermore, overexpression of G 13 in G 12/13 -deficient cells expressing the GABA B receptor showed the recovery of JNK activation mediated by the GABA B receptor (Fig. 2C). Whereas ERK1/2 activation induced by baclofen was not changed in WT MEFs, G 12/13 -deficient cells expressing the GABA B receptor cotransfected without or with G 13 . Together, these results indicated that G 13 was necessary for GABA B receptor-mediated JNK phosphorylation. The recovery of JNK activation was also observed during ...
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... activation induced by baclofen was not changed in WT MEFs, G 12/13 -deficient cells expressing the GABA B receptor cotransfected without or with G 13 . Together, these results indicated that G 13 was necessary for GABA B receptor-mediated JNK phosphorylation. The recovery of JNK activation was also observed during overexpression of G 12 ( fig. S2E). Because G 12 and G 13 have similar functions (43), we focused here on the G 13 ...
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... we confirmed that baclofen can also induce Rac1 activation in HEK293 cells (fig. S4B). Cotransfection of a dominantnegative mutant for Rac1 (Rac1N17) with GABA B receptor in HEK293 cells resulted in the inhibition of baclofen-induced JNK activation ( fig. S4C). These data further demonstrated that the GABA B receptor activates Rac1 to induce JNK ...
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Background:
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Citations
... γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system, and GABAb receptors are members of the receptor superfamily that includes mGlu receptors. Coupling of the GABAb receptor to a G protein leads to a decrease in calcium, an increase in potassium membrane conductance, and inhibition of cAMP formation [30,31]. Receptor tyrosine kinase (RTK) is a membrane protein containing extracellular ligand-binding regions, transmembrane segments, and intracellular tyrosine kinase domains. ...
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... KEGG pathway enrichment analysis showed that the differentiall expressed proteins in hippocampus were involved in long-term potentiation, G13 signaling pathway, integrin signaling pathway, platelet activation, and MAPK signaling pathway. G13 signaling pathway is associated with epilepsy, depression, anxiety, mental retardation, and Alzheimer's disease, and GABAB receptor activates G13 protein pathway to promote neuroprotective mechanism [56]. Integrin-mediated signaling pathways involved in the regulation of gabaergic synapse, including NMDA receptor-dependent ischemic long-term potentiation in the hippocampus, are associated with epilepsy, schizophrenia, and anxiety [57]. ...
The effects of HNK, I5, and I6 on the expression of protein in hippocampus of depressed mice were studied by isobaric tags for relative and absolute quantitation (iTRAQ) to explore the mechanism of their antidepressant action. HNK, I5, and I6 were administered intragastric administration once a day in the morning for 7 days. The drug was subsequently discontinued for 7 days (without any treatment). On the 15th day, mice in each group were given the drug (1.0, 10.0, 30.0 mg/kg) intragastric stimulation and mouse hippocampal tissues were taken to perform iTRAQ to identify differentially expressed proteins, and bioinformatics was used to analyze the functional enrichment of the differentially expressed proteins. Compared with Ctr group, the number of differentially expressed proteins in HNK, I5, and I6 treatment groups was 158, 88, and 105, respectively. The three groups shared 29 differentially expressed proteins. In addition, compared with HNK group, the number of differentially expressed proteins in I5 and I6 groups was 201 and 203, respectively. A total of 47 and 56 differentially expressed proteins were co-expressed in I5 and I6 groups. Bioinformatics analysis showed that these differentially expressed proteins mainly had the functions of binding, biocatalysis, and transport, and mainly participated in cellular process, biological regulation process, biological metabolism process, and stress reaction process. GO and KEGG pathway analysis found that these differentially expressed proteins were involved long-term potentiation, G13 pathway, platelet activation pathway, and MAPK signaling pathway. HNK, I5, and I6 antidepressants are closely related to sudden stress sensitivity, stress resistance, neurotransmitter, and metabolic pathways. This study provides a scientific basis to further elucidate the mechanism and clinical application of HNK, I5, and I6 antidepressants.
... It is possible mGluR7 may be capable of coupling to other G proteins, but our assay would only sense this if more efficient activation of mGluR7 could be achieved. In apparent contrast to the GABAB receptor (30), none of the mGluRs showed detectable activation through G13, and none showed activation of G14 or the Gs family. ...
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... Secretion of brain-derived neurotrophic factor Increase [230] Increase [55] P38/MAPK signaling Enhance [230] Enhance [55] The activity of ERK Enhance [231] Enhance [232] The activity of phosphorylated JNK Enhance [233] Enhance [234] Abbreviations: G protein-coupled inwardly-rectifying potassium channel, GIRK; mitogen-activated protein kinase, MAPK; extracellular signal-regulated kinase, ERK; c-Jun N-terminal kinase, JNK. ...
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... Secretion of brain-derived neurotrophic factor Increase [230] Increase [55] P38/MAPK signaling Enhance [230] Enhance [55] The activity of ERK Enhance [231] Enhance [232] The activity of phosphorylated JNK Enhance [233] Enhance [234] Abbreviations: G protein-coupled inwardly-rectifying potassium channel, GIRK; mitogen-activated protein kinase, MAPK; extracellular signal-regulated kinase, ERK; c-Jun N-terminal kinase, JNK. ...
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The main neurotransmitter in the brain responsible for the inhibition of neuronal activity is γ-aminobutyric acid (GABA). It plays a crucial role in circuit formation during development, both via its primary effects as a neurotransmitter and also as a trophic factor. The GABAB receptors (GABABRs) are G protein-coupled metabotropic receptors; on one hand, they can influence proliferation and migration; and, on the other, they can inhibit cells by modulating the function of K+ and Ca2+ channels, doing so on a slower time scale and with a longer-lasting effect compared to ionotropic GABAA receptors. GABABRs are expressed pre- and post-synaptically, at both glutamatergic and GABAergic terminals, thus being able to shape neuronal activity, plasticity, and the balance between excitatory and inhibitory synaptic transmission in response to varying levels of extracellular GABA concentration. Furthermore, given their subunit composition and their ability to form complexes with several associated proteins, GABABRs display heterogeneity with regard to their function, which makes them a promising target for pharmacological interventions. This review will describe (i) the latest results concerning GABABRs/GABABR-complex structures, their function, and the developmental time course of their appearance and functional integration in the brain, (ii) their involvement in manifestation of various pathophysiological conditions, and (iii) the current status of preclinical and clinical studies involving GABABR-targeting drugs.
... Baclofen has the potential to reduce craving and prevent relapse in AUD (Bschor et al. 2018;Morley et al. 2018;van den Brink 2020), and it could be a useful alternative at the initiation of detoxification to reduce the need for benzodiazepines in the acute phase of withdrawal (Cooney et al. 2019). Activation of the GABA-B receptor provides a negative feedback loop that counteracts the downregulation of the GABA system, including GABA-A receptors, and has been proposed for being partly neuroprotective, worth to be explored in the prevention of alcohol-related brain damage (Cooney et al. 2019;Wang et al. 2021). Baclofen is contraindicated in patients with severe kidney disease and in pregnant women (pregnancy category C). ...
Introduction
Alcohol-use disorders (AUD) have a high global prevalence and about half of the patients suffering from AUD will develop withdrawal symptoms upon cessation of alcohol intake. Therefore, management of alcohol withdrawal has a significant place in medical care. The current gold standard for the prevention and treatment of the alcohol withdrawal syndrome is the GABA-A agonist diazepam [1]. Because of side-effects like high sedation, risk of respiratory depression, its addictive properties and possible liver impairment, alternative pharmacological treatment options are desirable. Baclofen, a GABA-B agonist prescribed for the treatment of spasticity, seems like a promising agent to act as such an alternative. More recently, its off-label use has found its place in the management of alcohol-use disorder because of its anti-craving properties [2]. Given its effects on the GABA system and it lacking the negative aspects of diazepam, baclofen could be a viable treatment alternative in managing alcohol withdrawal. Promising results from studies by Addolorato and Lyon, included in a recent Cochrane review, substantiate the above claim [3]. Moreover, as baclofen treatment can be continued to counter craving, it can offer a simplification of the pharmacological treatment of alcohol-use disorder as a whole.
Goal
The current study investigates the use of baclofen compared to placebo in the management of AUD, and additionally explores the possible dose-effect relation of baclofen in reducing alcohol craving.
Method
A single-blinded randomized placebo-controlled trial is being conducted with three arms (placebo, baclofen 30 mg/day and baclofen 60 mg/day) in 90 treatment-seeking AUD patients, for 7 consecutive days. During the study, patients can receive additional diazepam as-needed by protocol, primarily based on the Clinical Institute Withdrawal Assessment for Alcohol Revised (CIWA-ar) scale score. Assessment takes place every two hours during the first three days, and every four hours during the last four days. The primary outcome measure is the amount of patients who received additional diazepam during these 7 days, analyzed using a Chi-Square test. Secundary outcome measures include the amount of additional diazepam, analyzed with ANOVA.
Results
So far, 29 patients were included in the study. Fewer patients receiving baclofen 60 mg/dayneeded additional diazepam (2 out of 12) compared to those receiving either baclofen 30 mg/day (3 out of 8) or placebo (6 out of 9), but this did not reach statistical significance (p = 0.061). The mean amount of diazepam needed per patient was 10 mg for placebo, 5 mg for baclofen 30 mg/day and 1.67 mg for baclofen 60 mg/day (p = 0.091).
Conclusion
These preliminary findings show that baclofen in a dose of 60 mg/day, may be a useful alternative to diazepam in treatment-seeking AUD patients during alcohol withdrawal. Further inclusion of patients will demonstrate if this trend is carried on and if there’s a significant difference to be found.
Guipi wan (GPW) is a traditional Chinese medicine commonly used in clinical practice, typically to treat neurological diseases such as neurasthenia and traumatic brain injury. It may have positive effects on cerebral ischemia‒reperfusion injury (cI/R). This study aimed to assess the effects of GPW in a mouse model of cI/R and find its possible targets. C57BL/6J mice were used to establish the cI/R model, and the laser speckle doppler was used to determine the success of the model. GPW was administered intragastrically for 7 days, brain tissue sections were stained with TTC, HE, and TUNEL, Western blot assay was performed to detect the effect of apoptosis-related proteins. Furthermore, we screened active ingredients from the TCM Database and constructed a compound‒target network using the Cytoscape 3.8.0 software. Moreover, we employed protein‒protein interaction and component‒target‒pathway network analyses to determine the potential components of GPW and its target genes, the key target was verified through molecular docking. Finally, we detected the influence of the downstream signaling pathway of the target through Western blot. The results showed that GPW decreased the cerebral infarction area, neurological function scores, and neuronal apoptosis in mice by regulating PI3K/AKT signaling pathway. Network analysis indicated that gamma-aminobutyric acid B receptor 1 (GABBR1) might be a potential target for the treatment of cI/R. Molecular docking indicated that 9 active components in GPW could bind to GABBR1 with desirable binding energy. This study represented the demonstratable effect of GPW in the treatment of cI/R injury and suggested GABBR1 as a potential target using network analysis.
Metabotropic glutamate receptors (mGluRs) are obligate dimer G protein coupled receptors that can all function as homodimers. Here, each mGluR homodimer was examined for its G protein coupling profile using a bioluminescence resonance energy transfer-based assay that detects the interaction between a split YFP-tagged Gβ 1γ2 and a Nanoluciferase tagged free Gβγ sensor, MAS-GRK3-ct- nanoluciferase with 14 specific Gα proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2 and 3 and 4, 6, 7, and 8, respectively) are thought to couple to Gi/o exclusively. In addition, the group I mGluRs (1 and 5) are known to couple to the Gq/11 family and generally thought to also couple to the pertussis toxin-sensitive Gi/o family some reports have suggested Gs coupling is possible as cAMP elevations have been noted. In this study, coupling was observed with all eight mGluRs through the Gi/o proteins and only mGluR1 and mGluR5 through Gq/11, and, perhaps surprisingly, not G14 None activated any Gs protein. Interestingly, coupling was seen with the group I and II but not the group III mGluRs to G16 Slow but significant coupling to Gz was also seen with the group II receptors. SIGNIFICANCE STATEMENT: Metabotropic glutamate receptor (mGluR)-G protein coupling has not been thoroughly examined, and some controversy remains about whether some mGluRs can activate Gαs family members. Here we examine the ability of each mGluR to activate representative members of every Gα protein family. While all mGluRs can activate Gαi/o proteins, only the group I mGluRs couple to Gαq/11, and no members of the family can activate Gαs family members, including the group I receptors alone or with positive allosteric modulators.
Baclofen may reduce the symptoms of alcohol withdrawal, as an alternative or as an adjuvant for benzodiazepines, but the available data are insufficient to support baclofen-assisted alcohol withdrawal. This study investigated the need for diazepam during acute alcohol withdrawal in patients receiving baclofen. In a single-blind, dose-dependent randomized controlled trial with three study arms, 63 patients with alcohol use disorder, starting in-patient benzodiazepine-assisted alcohol detoxification, were randomly assigned to receive placebo (n = 18), baclofen 30 mg/day (N = 20), or baclofen 60 mg/day (N = 25) for 7 days. Diazepam was provided as needed based on the withdrawal symptoms stated by Clinical Institute Withdrawal Assessment for Alcohol-revised. The primary outcome measure was the number of patients in need of diazepam during alcohol detoxification. Secondary outcome measure included the between-group difference in the amount of diazepam needed during alcohol detoxification. Using baclofen 60 mg/day, 32% of patients needed additional diazepam compared to 35% on baclofen 30 mg/day and compared to 72% on placebo (P = .013). The median total amount of diazepam needed was significantly lower in patients receiving baclofen 60 mg/day (0 ± 10 mg diazepam) and baclofen 30 mg/day (0 ± 10 mg diazepam) compared to placebo (10 ± 43 mg diazepam; P = .017). Adverse events were comparable between patients on baclofen and placebo. Baclofen can reduce the withdrawal symptoms during alcohol detoxification. Baclofen was well tolerated and may be considered for the management of alcohol withdrawal syndrome, especially useful in situations where benzodiazepines should be withheld, such as patients with liver impairment.
