• Nutrition Research and Practice
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• v.7 no.1
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• pp.15-21
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• 2013

Leaf of Sasa borealis, a species of bamboo, has been reported to exhibit anti-hyperglycemic effect. However, its antidiabetic mechanism is not fully understood. In this study, we examined whether an extract of S. borealis activates AMP-activated protein kinase (AMPK) and exerts anti-hyperglycemic effects. Treatment with the S. borealis extract increased insulin signaling and phosphorylation of AMPK and stimulated the expression of its downstream targets, including $PPAR{\alpha}$, ACO, and CPT-1 in C2C12 cells and $PPAR{\alpha}$ in HepG2 cells. However, inhibition of AMPK activation attenuated insulin signaling and prevented the stimulation of AMPK target genes. The S. borealis extract increased glucose uptake in C2C12 cells and suppressed expression of the gluconeogenic gene, PEPCK in HepG2 cells. The extract significantly reduced blood glucose and triglyceride levels in STZ-induced diabetic mice. The extract enhanced AMPK phosphorylation and increased Glut-4 expression in the skeletal muscle of the mice. These findings demonstrated that the S. borealis extract exerts its anti-hyperglycemic effect through activation of AMPK and enhancement of insulin signaling.

• Molecules and Cells
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• v.27 no.6
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• pp.629-634
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• 2009

G protein-coupled receptors (GPCRs) are part of multi-protein networks called 'receptosomes'. These GPCR interacting proteins (GIPs) in the receptosomes control the targeting, trafficking and signaling of GPCRs. PDZ domain proteins constitute the largest protein family among the GIPs, and the predominant function of the PDZ domain proteins is to assemble signaling pathway components into close proximity by recognition of the last four C-terminal amino acids of GPCRs. We present here a machine learning based approach for the identification of GPCR-binding PDZ domain proteins. In order to characterize the network of interactions between amino acid residues that contribute to the stability of the PDZ domain-ligand complex and to encode the complex into a feature vector, amino acid contact matrices and physicochemical distance matrix were constructed and adopted. This novel machine learning based method displayed high performance for the identification of PDZ domain-ligand interactions and allowed the identification of novel GPCR-PDZ domain protein interactions.

• Molecules and Cells
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• v.47 no.1
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• pp.100004.1-100004.11
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• 2024

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

• Molecules and Cells
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• v.37 no.12
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• pp.881-887
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• 2014

Cell proliferation is tightly controlled by the cell-cycle regulatory proteins, primarily by cyclins and cyclin-dependent kinases (CDKs) in the $G_1$ phase. The ankyrin repeat-rich membrane spanning (ARMS) scaffold protein, also known as kinase D-interacting substrate of 220 kDa (Kidins 220), has been previously identified as a prominent downstream target of neurotrophin and ephrin receptors. Many studies have reported that ARMS/Kidins220 acts as a major signaling platform in organizing the signaling complex to regulate various cellular responses in the nervous and vascular systems. However, the role of ARMS/Kidins220 in cell proliferation and cell-cycle progression has never been investigated. Here we report that knockdown of ARMS/Kidins220 inhibits mouse neuroblastoma cell proliferation by inducing slowdown of cell cycle in the $G_1$ phase. This effect is mediated by the upregulation of a CDK inhibitor p21, which causes the decrease in cyclin D1 and CDK4 protein levels and subsequent reduction of pRb hyperphosphorylation. Our results suggest a new role of ARMS/Kidins220 as a signaling platform to regulate tumor cell proliferation in response to the extracellular stimuli.

• Molecules and Cells
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• v.28 no.1
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• pp.25-30
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• 2009

${\beta}$-Arrestins turn off G protein-mediated signals and initiate distinct G protein-independent signaling pathways. We previously demonstrated that angiotensin $AT_1$ receptorbound ${\beta}$-arrestin 1 is cleaved after $Phe^{388}$ upon angiotensin II stimulation. The mechanism and signaling pathway of angiotensin II-induced ${\beta}$-arrestin cleavage remain largely unknown. Here, we show that protein Tyr phosphatase activity is involved in the regulation of ${\beta}$-arrestin 1 cleavage. Tagging of green fluorescent protein (GFP) either to the N-terminus or C-terminus of ${\beta}$-arrestin 1 induced conformational changes and the cleavage of ${\beta}$-arrestin 1 without angiotensin $AT_1$ receptor activation. Orthovanadate and molybdate, inhibitors of protein Tyr phosphatase, attenuated the cleavage of C-terminal GFP-tagged ${\beta}$-arrestin 1 in vitro. The inhibitory effects of okadaic acid and pyrophosphate, which are inhibitors of protein Ser/Thr phosphatase, were less than those of protein Tyr phosphatase inhibitors. Cell-permeable pervanadate inhibited angiotensin II-induced cleavage of ${\beta}$-arrestin 1 in COS-1 cells. Our findings suggest that Tyr phosphorylation signaling is involved in the regulation of angiotensin II-induced ${\beta}$-arrestin cleavage.

• Journal of Life Science
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• v.19 no.11
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• pp.1506-1513
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• 2009

RGS proteins have been identified as negative regulators of G protein signalling pathways and attenuate the activity of GPCR receptors. However, information on the regulatory effects of RGS proteins in the activity of cannabinoid receptors is limited. In this study, the role of RGS proteins on the signal transduction of the CB2 cannabinoid receptor was investigated in HEK293 cells co-transfected with CB2-receptors and plasmids encoding RGS2, RGS3, RGS4 and RGS5. Treatment of cells with WIN55, 212-2, a CB2 receptor agonist, inhibited forskolin-induced cAMP response element (CRE) activity in CB2-transfected HEK293 (CB2-HEK293) cells. This inhibitory effect of WIN 55, 212-2 on CRE activity was reversed by co-transfection of CB2-HEK293 cells with RGS3, but not with RGS2, RGS4 and RGS5. However, endogenous RGS3 protein knocked down by a small interfering siRNA targeting RGS3 gene enhanced inhibition of forskolin induced CRE activity via agonist induced CB2 receptor signal transduction. These results indicate the functional role of endogenous RGS protein in cannabinoid signaling pathways and define receptor-selective roles of endogenous RGS3 in modulating CRE transcriptional responses to agonist induced CB2 receptor activity.

• KSBB Journal
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• v.25 no.6
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• pp.507-512
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• 2010

In this study, we investigated the ability of luteolin, a plant derived flavonoid on hepatocarcinoma cell growth using HepG2 cell culture system. We found that luteolin increased the Smac/DIABLO releases, a mitochondrial protein that potentiates apoptosis. Luteolin also induced either transcriptional activity or expression of PPAR-gamma, a target of cancer growth that PPAR-gamma agonist sensitizes to apoptosis in certain cancer types. To find the possible upstream target molecules of PPAR-gamma activated by luteolin treatment, we used compound C, a specific inhibitor of AMP-activated protein kinase. Pre-treatment of Compound C significantly restored the activation or expression of PPAR-gamma stimulated by luteolin. This result indicated that AMPK signaling might be involved in the activation or expression of PPAR-gamma signaling pathway stimulated by luteolin. Moreover, we also found that luteolin inhibited the insulin-stimulated Akt phosphorylation as well as AICAR, a specific AMPK activator. These results propose that luteolin significantly induces cancer cell death through modulating survival signal pathways such as PPAR-gamma and Akt. AMPK signaling pathway may be an upstream regulator for survival signal pathways such as PPAR-gamma and Akt stimulated by luteolin.

• The Korean Journal of Pain
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• v.31 no.2
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• pp.73-79
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• 2018

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to ${\mu}$ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the ${\beta}$-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the ${\beta}$-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the ${\mu}$ receptor G protein pathway selective (${\mu}$-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased ${\mu}$ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.

• 대한약리학회:학술대회논문집
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• 2006.10a
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• pp.104.2-104.2
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• 2006

• Biomolecules & Therapeutics
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• v.25 no.1
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• pp.69-79
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• 2017

Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.