Characterization of a G Protein-Coupled Receptor for Nicotinic Acid

Lorenzen, Anna; Stannek, Christina; Lang, Heidrun; Andrianov, V. M.; Kalvinsh, Ivars; Schwabe, Ulrich

doi:10.1124/mol.59.2.349

Cited by 122 publications

(108 citation statements)

References 31 publications

(28 reference statements)

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“…The increases in [Ca 2 þ ] i were concentration dependent in the range of 10 À7 -10 À3 M (Figure 2a). Furthermore, triggering of changes in [Ca 2 þ ] i were caused by NA binding to its specific receptor because nicotinamide, a structurally related compound, which does not bind to GPR109A receptors, 12 (Figure 2c). These data suggested that all mature neutrophils express functional GPR109A receptors and also excluded the possibility that the NA-mediated effects on [Ca 2 þ ] i seen using the bulk spectrofluorometric assay were due to GPR109A-expressing contaminating cells.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

et al. 2007

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“…The membranes were prepared as previously described [71][72][73]. Briefly, cerebella were dissected and homogenized in nine volumes of ice-cold 0.32 M sucrose with a glass Teflon homogenizer.…”

Section: -Nitrophenylcarbamic Acid Cyclohexyl Ester (52)mentioning

confidence: 99%

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

Minkkilä

Myllymäki

Saario

et al. 2009

European Journal of Medicinal Chemistry

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“…The animals lived in a 12-h light/12-h dark cycle (lights on at 0700 h), with water and food available ad libitum. The rats were decapitated, 8 h after lights on (1500 h), whole brains were removed, dipped in isopentane on dry ice and stored at À80 C. Membranes were prepared as previously described [60][61][62].…”

Section: Animals and Preparation Of Rat Cerebellar Membranes For Mgl mentioning

confidence: 99%

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Myllymäki¹,

Käsnänen

Kataja³

et al. 2009

European Journal of Medicinal Chemistry

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Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)-and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

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Characterization of a G Protein-Coupled Receptor for Nicotinic Acid

Cited by 122 publications

References 31 publications

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

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