Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist

Młyniec, Katarzyna; Starowicz, Gabriela; Gaweł, Magdalena; Frąckiewicz, Ewelina; Nowak, Gabriel

doi:10.1016/j.jad.2016.05.007

Cited by 33 publications

(37 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CEBPB is also indicated to be a transcription factor for the expression of itself [84] and GPR39 [31], thereby presumably extrapolating CEBPB autostimulation-boosted reciprocal upregulation between CEBPB and GPR39. Notably, TC-G 1008, an agonist of GPR39 [34] enhanced the expression of GPR39 ( Figure 2B,H) in agreement with the observation in vivo [35]. This can be caused by CEBPB upregulated by TC-G 1008-mediated GPR39 agonism ( Figure 2G,H).…”

Section: Discussionsupporting

confidence: 86%

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

Goto¹,

Nishitsuji²,

Sugiyama³

et al. 2020

IJMS

View full text Add to dashboard Cite

Hepatitis B virus (HBV), a highly persistent pathogen causing hepatocellular carcinoma (HCC), takes full advantage of host machinery, presenting therapeutic targets. Here we aimed to identify novel druggable host cellular factors using the reporter HBV we have recently generated. In an RNAi screen of G protein-coupled receptors (GPCRs), GPCR39 (GPR39) appeared as the top hit to facilitate HBV proliferation. Lentiviral overexpression of active GPR39 proteins and an agonist enhanced HBV replication and transcriptional activities of viral promoters, inducing the expression of CCAAT/enhancer binding protein (CEBP)-β (CEBPB). Meanwhile, GPR39 was uncovered to activate the heat shock response, upregulating the expression of proviral heat shock proteins (HSPs). In addition, glioma-associated oncogene homologue signaling, a recently reported target of GPR39, was suggested to inhibit HBV replication and eventually suppress expression of CEBPB and HSPs. Thus, GPR39 provirally governed intracellular circuits simultaneously affecting the carcinopathogenetic gene functions. GPR39 and the regulated signaling networks would serve as antiviral targets, and strategies with selective inhibitors of GPR39 functions can develop host-targeted antiviral therapies preventing HCC.

show abstract

Section: Discussionsupporting

confidence: 86%

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

Goto¹,

Nishitsuji²,

Sugiyama³

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…TC-G 1008, a newly synthesized compound based on 2-pyridylpyrimidines, has been shown to increase the level of GLP-1 [9]. Recent research reveals that the administration of TC-G 1008 exerts an anti-depressive effect in animal experiments [15]. These evidences indicate that TC-G 1008-mediated GPR39 activation could have different roles in various cell types, but these studies all agree that TC-G 1008 is a highly specific agonist of the GPR39 receptor.…”

Section: Discussionmentioning

confidence: 99%

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

Chai

Zhang

Chang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

View full text Add to dashboard Cite

Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis. ARTICLE HISTORY

show abstract

“…GPR39 is downregulated in the frontal cortex and hippocampus of Zn 2+ -deficient rodents and suicide victims [13], but upregulated after chronic antidepressant treatment [22]. Furthermore, anxiety-and depressive-like behaviors were reported in Gpr39 knockout mice [23], and an antidepressant response was observed following a Gpr39 agonist treatment in wild-type mice [23,24]. In both of these studies, lack of Gpr39 was accompanied by decreased Creb and Bdnf expression, while Gpr39 agonist increased Bdnf expression [23,24]; these two proteins are widely associated with psychiatric disorders, including alcohol abuse [25].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice

Carlson

Ford

Carlson

et al. 2019

Neuropsychopharmacol.

View full text Add to dashboard Cite

Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn 2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist "wash out". As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.

show abstract

Potential antidepressant-like properties of the TC G-1008, a GPR39 (zinc receptor) agonist

Cited by 33 publications

References 41 publications

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice

Contact Info

Product

Resources

About