Molecular Identification of High and Low Affinity Receptors for Nicotinic Acid

Abstract

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia producing a desirable normalization of a range of cardiovascular risk factors, including a marked elevation of high density lipoprotein and a reduction in mortality. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a G i -G proteincoupled receptor may contribute. Utilizing available information on the tissue distribution of nicotinic acid receptors, we identified candidate orphan receptors. The selected orphan receptors were screened for responses to nicotinic acid, in an assay for activation of G i -G proteins. Here we describe the identification of the G protein-coupled receptor HM74 as a low affinity receptor for nicotinic acid. We then describe the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptor for nicotinic acid and other compounds with related pharmacology. The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia.

Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

“…Activation of GPR109A receptors occurs in an NA concentration range between 10 À7 and 10 À4 M, whereas GPR109B receptors require 10 À3 M NA for activation. 2 Therefore, mature neutrophils express GPR109A receptors, since significant signal transduction (changes in [Ca 2 þ ] i ) and apoptosis induction was seen at 10 À5 M NA. However, we cannot exclude the possibility that these cells additionally express GPR109B receptors, in particular, since the antibody used to measure protein expression may recognize both receptors.…”

“…The two receptors are highly homologous, displaying 96% identity at the protein level. 2 Neutrophil apoptosis has previously been reported to be regulated by cAMP. For instance, agents and inflammatory stimuli that increase cAMP levels delayed spontaneous neutrophil apoptosis.…”

“…1,2 NA is used to modify lipoprotein profiles in humans, resulting in a beneficial modification of multiple cardiovascular risk factors. 3 This highly desirable therapeutic profile of NA is due to its direct activation of GPR109A on the surface of adipocytes.…”

“…3 This highly desirable therapeutic profile of NA is due to its direct activation of GPR109A on the surface of adipocytes. 1 However, GPR109A mRNA is also highly expressed in spleen and lung tissues, 2 but it remains unclear which cells indeed express the receptor and whether it is functional. 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.…”

Effects of niacin supplementation (40 weeks) and two dietary levels of concentrate on performance, blood and fatty acid profiles of dairy cattle

“…Moreover, in humans NAM is a weak agonist to the receptor (HM74A), which exerts an antilipolytic action after stimulation with NA (Wise et al, 2003). Niehoff et al (2009a) noted that there is disagreement about the existence of NA in blood.…”