Human epidermoid A431 cells express functional nicotinic Acid receptor HM74a

Zhou, Lubing; Tang, Yuting; Cryan, Ellen V.; Demarest, Keith T.

doi:10.1007/s11010-006-9150-6

Cited by 12 publications

(18 citation statements)

References 16 publications

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“…20,21 Interestingly, elevation of cAMP promotes apoptosis in T cells, 26,27 suggesting cell-type-specific differences. In agreement to previously published work performed in cell lines, 28,29 we also observed reduced cAMP levels upon NA-mediated triggering of GPR109A receptors in mature neutrophils. This suggested a potential link to the NA-mediated pro-apoptotic effect observed in these cells.…”

Section: Discussionsupporting

confidence: 93%

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

et al. 2007

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G protein-coupled receptor (GPR)109A (HM74A) is a G i protein-coupled receptor, which is activated by nicotinic acid (NA), a lipidlowering drug. Here, we demonstrate that mature human neutrophils, but not eosinophils, express functional GPR109A receptors. The induction of the GPR109A gene appears to occur late in the terminal differentiation process of neutrophils, since a mixed population of immature bone marrow neutrophils did not demonstrate evidence for its expression. NA accelerated apoptosis in cultured neutrophils in a concentration-dependent manner, as assessed by phosphatidylserine redistribution, caspase-3 activation, and DNA fragmentation assays. The pro-apoptotic effect of NA was abolished by pertussis toxin, which was used to block G i proteins, suggesting a receptor-mediated mechanism. Activation of GPR109A by NA resulted in decreased levels of cyclic adenosine monophosphate (cAMP), most likely due to G i -mediated inhibition of adenylyl cyclase activity. NAinduced apoptosis was reversed by the addition of cell-permeable cAMP, pointing to the possibility that reduced cAMP levels promote apoptosis in neutrophils. Distal mechanism involved in this process may include the post-translational modification of members of the Bcl-2 family, such as dephosphorylation of pro-apoptotic Bad and antiapoptotic Mcl-1 proteins. Taken together, following maturation in the bone marrow, neutrophils express functional GPR109A receptors, which might be involved in the regulation of neutrophil numbers. Moreover, this study identified a new cellular target of NA and future drugs activating GPR109A receptors, the mature neutrophil.

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Section: Discussionsupporting

confidence: 93%

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

et al. 2007

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“…On the mRNA level, HCA 2 receptor expression has been shown in primary human keratinocytes (Maciejewski-Lenoir et al, 2006;Tang et al, 2008); however, immunohistochemistry failed to demonstrate HCA 2 receptor expression in keratinocytes (Maciejewski-Lenoir et al, 2006). Expression of the HCA 2 receptor in keratinocytes has recently been shown by genetic and functional approaches , and strong HCA 2 receptor expression has also been described in the human epidermoid carcinoma cell line A431 (Maciejewski-Lenoir et al, 2006;Zhou et al, 2007). Similar to macrophages, expression of the HCA 2 receptor in keratinocytes and keratinocyte cell lines is induced be IFN-␥ (Tang et al, 2008).…”

Section: B Hcamentioning

confidence: 99%

“…In adipocytes, a decrease in cAMP results in an antilipolytic effect because cAMP is the major intracellular regulator of lipolysis by stimulating cAMP-dependent kinase to activate lipolytic enzymes (Duncan et al, 2007). Also, in human neutrophils as well as in the human epidermoid cell line A431, activation of the HCA 2 receptor has been shown to result in decreased cAMP levels (Zhou et al, 2007;Kostylina et al, 2008 suggested that the decrease in cAMP levels induced by activation of the HCA 2 receptor in neutrophils induces apoptosis through a reduction in phosphorylation of the proapoptotic protein Bad via cAMP-dependent protein kinase.…”

Section: B Downstream Signalingmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Offermanns¹,

Colletti²,

Lovenberg³

et al. 2011

Pharmacol Rev

156

117

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“…1b, in response to acifran treatment, activation of ERK1/2 signaling was detected in a dose-dependent manner with an EC 50 of 178 nM for GPR109A and an EC 50 of 466 nM for GPR109B. In addition, to better characterize the GPR109A-mediated ERK1/2 signaling pathway, we also used the A431 cell line, a human epidermoid cell line with high endogenous expression levels of functional GPR109A receptors (24). A431 cells were cultured in serum-free DMEM for 24 h followed by stimulation with various concentrations of niacin in fresh serum-free DMEM for 5 min, and the concentration-dependent activation of ERK1/2 signaling was detected with an EC 50 of 3.43 M (Fig.…”

Section: Gpr109a Activates Erk1/2 Signaling Via Mek1/2 By Niacinmentioning

confidence: 99%

“…In the present study, we used four cellular backgrounds to characterize the mechanistic details of coupling of the human GPR109A to the ERK1/2 signaling pathway: HEK-293; CHO-K1; COS-7, which recombinantly express human GPR109A receptors; and A431 cells, a human epidermoid carcinoma cell line that endogenously expresses functional human GPR109A receptors (24). We document here, for the first time, the molecular mechanisms underlying the coupling of the human GPR109A to the ERK1/2 mitogen-activated protein kinase pathway in CHO-K1 and A431 cells and implicate the G i protein-initiated PKC and PDGFR/EGFR transactivation-dependent pathways.…”

mentioning

confidence: 99%

Distinct Kinetic and Spatial Patterns of Protein Kinase C (PKC)- and Epidermal Growth Factor Receptor (EGFR)-dependent Activation of Extracellular Signal-regulated Kinases 1 and 2 by Human Nicotinic Acid Receptor GPR109A

Li¹,

Deng

Chun

et al. 2011

Journal of Biological Chemistry

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Nicotinic acid (niacin) has been widely used as a lipid-lowering drug for several decades, and recently, orphan G proteincoupled receptor GPR109A has been identified as a receptor for niacin. Mechanistic investigations have shown that, upon niacin activation, GPR109A couples to a G i protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for GPR109A signaling remain largely unknown. Using CHO-K1 cells stably expressing GPR109A and A431 cells, which are a human epidermoid cell line with high levels of endogenous expression of functional GPR109A receptors, we found that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by niacin was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that GPR109A induced ERK1/2 activation via the matrix metalloproteinase/epidermal growth factor receptor transactivation pathway at both early and later time points (2-5 min); this pathway was distinct from the PKC pathway-mediated ERK1/2 phosphorylation that occurs at early time points (<2 min) in response to niacin. Overexpression of G␤␥ subunit scavengers ␤ARK1-CT and the G␣ subunit of transducin led to a significant reduction of ERK1/2 phosphorylation, suggesting a critical role for ␤␥ subunits in GPR109A-activated ERK1/2 phosphorylation. Using arrestin-2/3-specific siRNA and an internalization-deficient GPR109A mutant, we found that arrestin-2 and arrestin-3 were not involved in GPR109A-mediated ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to niacin GPR109A receptors initially activate G i , leading to dissociation of the G␤␥ subunit from activated G i , and subsequently induce ERK1/2 activation via two distinct pathways, one PKC-dependent pathway occurring at a peak time of <2 min and the other matrix metalloproteinase-dependent growth factor receptor transactivation occurring at both early and later time points (2-5 min).Nicotinic acid (niacin), a B group vitamin, has been demonstrated to be the first pharmacologic agent that is able to clinically modify plasma lipids favorably (1, 2). Previous clinical studies have revealed that niacin has the abilities to lower levels of total plasma cholesterol, free fatty acids, and triglycerides and to strongly raise high density lipoprotein cholesterol compared with other lipid-lowering drugs (3, 4). In addition, niacin has been shown to effectively reduce the progression of atherosclerosis and mortality from coronary heart disease. However, its exact mechanism was not understood until the orphan receptor GPR109A (HM74a in human and protein up-regulated in macrophages by IFN-␥ (PUMA-G) in mice) was identified as a receptor for niacin in 2003 (5-7). Niacin-mediated activation of GPR109A functions in a G protein-coupled manner to decrease cAMP production, resulting in decreased hormone-sensitive lipase activity and reduced hydrolysis of trigl...

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Human epidermoid A431 cells express functional nicotinic Acid receptor HM74a

Cited by 12 publications

References 16 publications

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

Distinct Kinetic and Spatial Patterns of Protein Kinase C (PKC)- and Epidermal Growth Factor Receptor (EGFR)-dependent Activation of Extracellular Signal-regulated Kinases 1 and 2 by Human Nicotinic Acid Receptor GPR109A

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