Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A).
G protein-coupled receptor (GPR)109A (HM74A) is a G(i) protein-coupled receptor, which is activated by nicotinic acid (NA), a lipid-lowering 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. NA-induced 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.
Kostylina
G
G
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, Bern, Switzerland.
Simon
D
D
Fey
M F
MF
Yousefi
S
S
Simon
H U
HU
D017209:Apoptosis; D000242:Cyclic AMP / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D009525:Niacin / Q000378:metabolism* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494819:BAD protein, human; C530636:HCAR2 protein, human; C473653:HCAR3 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D051025:bcl-Associated Death Protein; D009525:Niacin; D000242:Cyclic AMP