GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing

Benyó, Zoltán; Gille, Andreas; Kero, Jukka; Csiky, M; Suchánková, Marie Catherine; Nüsing, Rolf M.; Moers, Alexandra; Pfeffer, Klaus; Offermanns, Stefan

doi:10.1172/jci23626

Cited by 312 publications

(299 citation statements)

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“…Recently, it has been demonstrated that the receptor is also expressed on macrophages and dendritic cells, but not on monocytes. 4 Therefore, GPR109A receptors are expressed on some, but not all, leukocytes and may play a role in defense mechanisms against pathogens, at least within the innate immune system. NA binds to both low-(GPR109B; HM74) and high-affinity (GPR109A; HM74A) receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that interferon-g is able to induce GPR109A receptors in macrophages, and that NA is subsequently able to stimulate prostaglandin E2 and D2 synthesis in these cells. 4 The identification of functional GPR109A receptors in a cell outside adipose tissue raised the question whether additional cell types carry GPR109A receptors, which might also be targeted during therapy with NA.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 99%

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confidence: 99%

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

et al. 2007

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“…Recent work has begun to elucidate the mechanism by which nicotinic acid induces flushing (16 -19). GPR109A has been shown to mediate nicotinic acid-induced flushing through release of prostaglandin D2 (PGD 2 ) and involves the activation of the DP1 receptor and possibly a PGE 2 receptor (EP2 or EP4) (16,18) Recent work has further supported the hypothesis that it is GPR109A receptors on Langerhans cells in the skin that mediate nicotinic acid-induced flushing through generation of PGD 2 (17,19).…”

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confidence: 99%

Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors

Richman

Kanemitsu-Parks

Gaidarov

et al. 2007

Journal of Biological Chemistry

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Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a G i proteincoupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.Nicotinic acid (niacin, vitamin B3, pyridine-3-carboxylic acid) is the most effective therapeutic agent to date for raising high density lipoprotein (HDL) 2 levels. It also offers protection against other cardiovascular risk factors by lowering very low density lipoprotein (VLDL), low density lipoprotein (LDL), and lipoprotein(a) plasma concentrations (1, 2). Although the mechanism by which nicotinic acid raises HDL is not clear, one hypothesis is that it is the ability of nicotinic acid to inhibit lipolysis in adipocytes that results in a decrease in the concentration of free fatty acids available for the liver to use for triglyceride synthesis and VLDL production. The attenuated synthesis of the triglyceride-rich VLDL particles in the liver leads to a decreased rate of HDL metabolism via limiting the cholesterol ester transfer protein (CETP)-mediated exchange of cholesterol from HDL to VLDL, and triglyceride from VLDL to HDL (3-6). Another hypothesis is that nicotinic acid inhibits the uptake and subsequent catabolism of Apo-AI-containing HDL particles in hepatocytes (7,8).Identification of a high affinity nicotinic acid binding site that was localized to adipose, macrophage, and spleen tissues and appeared to function in a G i protein-coupled manner (9) led to the molecular identification of the high affinity nicotinic acid receptor GPR109A (HM74A in humans and PUMA-G in mice) (10 -12). In the adipose, GPR109A mediates an anti-lipolytic response that can attenuate cAMP-stimulated lipolysis (11). A low affinity nicotinic acid receptor ...

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“…In man, the flush response to niacin can be completely abolished by COX inhibitors such as aspirin or indomethacin (Svedmyr et al, 1977;Wilkin et al, 1982). In mice, the flush response to niacin can be eliminated by knocking out genes for either the niacin receptor or COX-1, consistent with an exclusive and obligatory role for this pathway in niacin-evoked skin flushing (Benyó et al 2005). Classical vasodilatory mediators, such as histamine, bradykinin, serotonin, and acetylcholine do undergo changes in their skin transudate levels after niacin challenge (Morrow et al, 1992;Plummer et al, 1977).…”

Section: Mediation Of Niacin Flush By Aa Metabolitesmentioning

confidence: 99%

“…Formation of AA is the rate-limiting step in the biosynthesis of the vasodilatory PGD 2 and E2 (PGE 2 ) (Murakami and Kudo 2004) These prostaglandins bind to specific prostanoid receptors on vascular smooth muscle within the skin. Activation of prostanoid receptors dilates cutaneous blood vessels (Lai et al, 2007), and a visible skin flush arises from the ensuing increased blood flow (Benyó et al, 2005;Maciejewski-Lenoir et al, 2006;Morrow et al, 1989Morrow et al, , 1992.…”

Section: Mechanism Of the Niacin Flush Responsementioning

confidence: 99%

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

Messamore

Yao

2015

OCL

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-This paper reviews the potential role of arachidonic acid in the pathophysiology of schizophrenia. We discuss how abnormal levels of arachidonic acid may arise, and how dysregulation of signaling molecules derived from it have the potential to disrupt not only dopamine signaling, but numerous other physiological processes associated with the illness. Pharmacological doses of niacin stimulate the release of arachidonic acid; and arachidonic acid-derived molecules in turn dilate blood vessels in the skin. A blunted skin flush response to niacin is reliably observed among patients with schizophrenia. The niacin response abnormality may thus serve as a biomarker to identify a physiological subtype of schizophrenia associated with defective arachidonic acid-derived signaling.Keywords: Phospholipids / arachidonic acid / eicosanoids / niacin-induced flushing, endophenotype marker / schizophrenia Résumé -Signalisation des phospholipides, de l'arachidonate et de l'écosanoïde dans la schizophrénie. Cet article examine le rôle potentiel de l'acide arachidonique dans la physiopathologie de la schizophrénie. Il est discuté comment des niveaux anormaux d'acide arachidonique peuvent survenir, et comment la dérégulation des molécules de signalisation qui en découle est capable de perturber non seulement la signalisation de la dopamine, mais aussi de nombreux autres processus physiologiques associés avec cette maladie. Des doses pharmacologiques de niacine stimulent la libération d'acide arachidonique ; des molécules dérivées de l'acide arachidonique dilatent à leur tour les vaisseaux sanguins dans la peau. Une brusque rougeur de la peau en réponse à la niacine est observée de manière constante parmi les patients atteints de schizophrénie. La réponse anormale à la niacine peut donc servir de biomarqueur afin d'identifier un sous-type physiologique de la schizophrénie, associé à un système défectueux de signalisation des dérivés de l'acide arachidonique.

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GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing

Cited by 312 publications

References 52 publications

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors

Phospholipid, arachidonate and eicosanoid signaling in schizophrenia

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