• Molecules and Cells
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• 제47권1호
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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.

• The Korean Journal of Physiology and Pharmacology
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• 제6권3호
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• pp.139-142
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• 2002

To examine intracellular signaling of human $S1P_3\;(hS1P_3),$ a sphingosine 1-phosphate (S1P) receptor in plasma membrane, $hS1P_3$ DNA was transfected into RH7777 rat hepatoma cell line, and the inhibition of forskolin-induced cAMP accumulation and activation of MAP kinases by S1P were tested. In $hS1P_3$ transformants, S1P inhibited forskolin-induced activation of adenylyl cyclase activity by about 80% and activated MAP kinases in dose-dependent and pertussis-toxin (PTX) sensitive manners. In oocytes expressing $hS1P_3$ receptor, S1P evoked $Cl^-$ conductance. These data suggested that PTX-sensitive G proteins are involved in $hS1P_3-mediated$ signaling, especially the positive action of S1P in cell proliferation. The potential advantages of rat hepatoma cells for the research of sphingosine 1-phosphate receptor are discussed.

• Asian Pacific Journal of Cancer Prevention
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• 제15권2호
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• pp.1041-1046
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• 2014

Evidence is growing that the $GABA_B$ receptor, which belongs to the G protein-coupled receptor (GPCR) superfamily, is involved in tumorigenesis. Recent studies have shown that ${\beta}$-arrestin can serve as a scaffold to recruit signaling protein c-Jun N-terminal knase (JNK) to GPCR. Here we investigated whether ${\beta}$-arrestin recruits JNK to the $GABA_B$ receptor and facilitates its activation to affect the growth of cancer cells. Our results showed that ${\beta}$-arrestin expression is decreased in breast cancer cells in comparison with controls. ${\beta}$-arrestin could enhance interactions of the $GABA_BR{\cdot}{\beta}-arrestin{\cdot}JNK$ signaling module in MCF-7 and T-47D cells. Further studies revealed that increased expression of ${\beta}$-arrestin enhances the phosphorylation of JNK and induces cancer cells apoptosis. Collectively, these results indicate that ${\beta}$-arrestin promotes JNK mediated apoptosis via a $GABA_BR{\cdot}{\beta}-arrestin{\cdot}JNK$ signaling module.

• The Korean Journal of Pain
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• 제31권2호
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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.

• Laboraroty Animal Research
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• 제34권4호
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• pp.140-146
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• 2018

Though bile acids have been well known as digestive juice, recent studies have demonstrated that bile acids bind to their endogenous receptors, including Farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1; TGR5) and serve as hormone to control various biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism, immune responses, and energy metabolism. Deficiency of those bile acid receptors has been reported to induce diverse metabolic syndromes such as obesity, hyperlipidemia, hyperglycemia, and insulin resistance. As consistent, numerous studies have reported alteration of bile acid signaling pathways in type II diabetes patients. Interestingly, bile acids have shown to activate TGR5 in intestinal L cells and enhance secretion of glucagon-like peptide 1 (GLP-1) to potentiate insulin secretion in response to glucose. Moreover, FXR has been shown to crosstalk with TGR5 to control GLP-1 secretion. Altogether, bile acid receptors, FXR and TGR5 are potent therapeutic targets for the treatment of metabolic diseases, including type II diabetes.

• Biomolecules & Therapeutics
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• 제25권3호
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• pp.239-248
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• 2017

Desensitization and acute tolerance are terms used to describe the attenuation of receptor responsiveness by prolonged or intermittent exposure to an agonist. Unlike desensitization of G protein-coupled receptors (GPCRs), which is commonly explained by steric hindrance caused by the ${\beta}$-arrestins that are translocated to the activated receptors, molecular mechanisms involved in the acute tolerance of GPCRs remain unclear. Our studies with several GPCRs and related mutants showed that the acute tolerance of GPCRs could occur independently of agonist-induced ${\beta}$-arrestin translocation. A series of co-immunoprecipitation experiments revealed a correlation between receptor tolerance and interactions among receptors, ${\beta}$-arrestin2, and $G{\beta}{\gamma}$. $G{\beta}{\gamma}$ displayed a stable interaction with receptors and ${\beta}$-arrestin2 in cells expressing GPCRs that were prone to undergo tolerance compared to the GPCRs that were resistant to acute tolerance. Strengthening the interaction between $G{\beta}{\gamma}$ and ${\beta}$-arrestin rendered the GPCRs to acquire the tendency of acute tolerance. Overall, stable interaction between the receptor and $G{\beta}{\gamma}$ complex is required for the formation of a complex with ${\beta}$-arrestin, and determines the potential of a particular GPCR to undergo acute tolerance. Rather than turning off the signal, ${\beta}$-arrestins seem to contribute on continuous signaling when they are in the context of complex with receptor and $G{\beta}{\gamma}$.

• The Korean Journal of Physiology and Pharmacology
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• 제17권2호
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• pp.139-147
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• 2013

Lysolipids such as LPA, S1P and SPC have diverse biological activities including cell proliferation, differentiation, and migration. We investigated signaling pathways of LPA-induced contraction in feline esophageal smooth muscle cells. We used freshly isolated smooth muscle cells and permeabilized cells from cat esophagus to measure the length of cells. Maximal contraction occurred at $10^{-6}M$ and the response peaked at 30s. To identify LPA receptor subtypes in cells, western blot analysis was performed with antibodies to LPA receptor subtypes. LPA1 and LPA3 receptor were detected at 50 kDa and 44 kDa. LPA-induced contraction was almost completely blocked by LPA receptor (1/3) antagonist KI16425. Pertussis toxin (PTX) inhibited the contraction induced by LPA, suggesting that the contraction is mediated by a PTX-sensitive G protein. Phospholipase C (PLC) inhibitors U73122 and neomycin, and protein kinase C (PKC) inhibitor GF109203X also reduced the contraction. The PKC-mediated contraction may be isozyme-specific since only $PKC{\varepsilon}$ antibody inhibited the contraction. MEK inhibitor PD98059 and JNK inhibitor SP600125 blocked the contraction. However, there is no synergistic effect of PKC and MAPK on the LPA-induced contraction. In addition, RhoA inhibitor C3 exoenzyme and ROCK inhibitor Y27632 significantly, but not completely, reduced the contraction. The present study demonstrated that LPA-induced contraction seems to be mediated by LPA receptors (1/3), coupled to PTX-sensitive G protein, resulting in activation of PLC, PKC-${\varepsilon}$ pathway, which subsequently mediates activation of ERK and JNK. The data also suggest that RhoA/ROCK are involved in the LPA-induced contraction.

• Biomolecules & Therapeutics
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• 제25권1호
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• pp.80-90
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• 2017

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, $S1P_{1-5}$. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

• The Korean Journal of Physiology and Pharmacology
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• 제14권3호
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• pp.145-150
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• 2010

Adenosine (Ado) is an important mediator of the endogenous defense against ischemia-induced injury in the heart. The action of Ado is mediated by activation of G protein-gated inwardly rectifying $K^+$ (GIRK) channels. In turn, GIRK channels are inhibited by reducing phosphatidylinositol 4,5-bisphosphate ($PIP_2$) through Gq protein-coupled receptors (GqPCRs). We previously found that GIRK channels activated by acetylcholine, a muscarinic M2 acetylcholine receptor agonist, are inhibited by GqPCRs in a receptor-specific manner. However, it is not known whether GIRK channels activated by Ado signaling are also regulated by GqPCRs. Presently, this was investigated in mouse atrial myocytes using the patch clamp technique. GIRK channels were activated by $100\;{\mu}M$ Ado. When Ado was repetitively applied at intervals of 5~6 min, the amplitude of second Ado-activated GIRK currents ($I_{K(Ado)}$) was $88.3{\pm}3.7%$ of the first $I_{K(Ado)}$ in the control. Pretreatment of atrial myocytes with phenylephrine, endothelin-1, or bradykinin prior to a second application of Ado reduced the amplitude of the second $I_{K(Ado)}$ to $25.5{\pm}11.6%$, $30.5{\pm}5.6%$, and $96.0{\pm}2.7%$, respectively. The potency of $I_{K(Ado)}$ inhibition by GqPCRs was different with that observed in acetylcholine-activated GIRK currents ($I_{K(ACh)}$) (endothelin-1>phenylephrine>bradykinin). $I_{K(Ado)}$ was almost completely inhibited by $500\;{\mu}M$ of the $PIP_2$ scavenger neomycin, suggesting low $PIP_2$ affinity of $I_{K(Ado)}$. Taken together, these results suggest that the crosstalk between GqPCRs and the Ado-induced signaling pathway is receptor-specific. The differential change in $PIP_2$ affinity of GIRK channels activated by Ado and ACh may underlie, at least in part, their differential responses to GqPCR agonists.

• Asian Pacific Journal of Cancer Prevention
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• 제14권8호
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• pp.4775-4778
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• 2013

The key signaling networks regulating cancer cell proliferation remain to be defined. The leucine-rich repeat containing G-protein coupled receptor 48 (GPR48) plays an important role in multiple organ development. In the present study, we investigated whether GPR48 functions in cancer cells using MCF-7, HepG2, NCI-N87 and PC-3 cells. We found that GPR48 overexpression promotes while its knockdown using small interfering RNA oligos inhibits cell proliferation. In addition, Wnt/${\beta}$-catenin signaling was activated in cells overexpressing GPR48. Therefore, our results indicated that GPR48 activates Wnt/${\beta}$-catenin signaling to regulate cancer cell proliferation.