1. ¹Department of Pharmacology, University of Bern, Bern, Switzerland
2. ²Department of Dermatology, University of Bern, Bern, Switzerland
3. ³Department of Medical Oncology, University of Bern, Bern, Switzerland

Correspondence: HU Simon, Department of Pharmacology, University of Bern, Friedbühlstrasse 49, Bern CH-3010, Switzerland. Tel: +41 31 632 3281; Fax: +41 31 632 4992; E-mail: hus@pki.unibe.ch

Received 26 April 2007; Revised 20 August 2007; Accepted 10 September 2007; Published online 12 October 2007.

Abstract

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.