title: Role of HCA₂ (GPR109A) in nicotinic acid and fumaric acid ester-induced effects on the skin.
abstract: Nicotinic acid (NA) and fumaric acid esters (FAE) such as monomethyl fumarate or dimethyl fumarate are drugs that elicit a cutaneous reaction called flushing as a side effect. NA is used to reduce progression of atherosclerosis through its anti-dyslipidemic activity and lipid-independent mechanisms involving immune cells, whereas FAE are used to treat psoriasis via largely unknown mechanisms. Both, NA and FAE, induce flushing by the activation of the G-protein-coupled receptor (GPCR) Hydroxy-carboxylic acid receptor 2 (HCA₂, GPR109A) in cells of the epidermis. While the wanted effects of NA are at least in part also mediated by HCA₂, it is currently not clear whether this receptor is also involved in the anti-psoriatic effects of FAE. The HCA₂-mediated flushing response to these drugs involves the formation of prostaglandins D₂ and E₂ by Langerhans cells and keratinocytes via COX-1 in Langerhans cells and COX-2 in keratinocytes. This review summarizes recent progress in the understanding of the mechanisms underlying HCA₂-mediated flushing, describes strategies to mitigate it and discusses the potential link between flushing, HCA₂ and the anti-psoriatic effects of FAE.
authors: Molecular Pharmacology, GIGA-Signal Transduction Unit, University of Liège, CHU B34, 4000 Liège, Belgium. J.Hanson@ulg.ac.be
authors: Julien
authors: J
authors: Hanson
authors: Andreas
authors: A
authors: Gille
authors: Stefan
authors: S
authors: Offermanns
mesh_terms: D000818:Animals; D005483:Flushing / Q000139:chemically induced*; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D009525:Niacin / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology; D011565:Psoriasis / Q000188:drug therapy; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D012867:Skin / Q000187:drug effects*
chemical_list: D005650:Fumarates; C530636:HCAR2 protein, human; D011453:Prostaglandins; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D011451:Prostaglandin-Endoperoxide Synthases