Differential tissue and ligand-dependent signaling of GPR109A receptor: Implications for anti-atherosclerotic therapeutic potential

Central GPR109A Activation Mediates Glutamate-Dependent Pressor Response in Conscious Rats

“…6 and 7). The latter findings agree with reported studies in other model systems (Maciejewski-Lenoir et al, 2006;Gaidarov et al, 2013). Equally important, NA failed to increase Ca 21 or glutamate levels in PC12 cells after siRNA-evoked GPR109A knockdown (Fig.…”

“…We hypothesized that NA activation of GPR109A in the RVLM leads to Ca 21 -dependent L-glutamate release because 1) NA (10 mM-3 mM) mediates a GPR109A-dependent increase in intracellular Ca 21 levels in macrophages and epidermal Langerhans cells (Benyo et al, 2005(Benyo et al, , 2006Vanhorn et al, 2012;Gaidarov et al, 2013), 2) Ca 21 triggers L-glutamate release (Kish and Ueda, 1991;Berridge, 1998;Sudhof, 2004), and 3) elevated L-glutamate levels cause oxidative stress (Wang et al, 2013;Yang et al, 2014), sympathoexcitation (Chapp et al, 2014), and ultimately BP elevation (Iwata et al, 1987;Bazil and Gordon, 1993). Therefore, the RVLM GPR109A most likely mediates a glutamate-dependent sympathoexcitation.…”

Inflammation stimulates niacin receptor (GPR109A/HCA2) expression in adipose tissue and macrophages

“…Specifi cally, niacin has been shown to suppress the increase in LDL uptake that is induced by LPS treatment in wild-type macrophages but not in macrophages defi cient in GPR109A/HCA2 ( 21 ). Additionally, niacin acting via GPR109A/HCA2 has been shown to stimulate cholesterol effl ux by increasing the expression of ABCA1, ABCG1, and CD36 (31)(32)(33). These results coupled with our results suggest that activation of GPR109A/HCA2 by niacin, endogenous ligand, or enhanced basal activity decreases the ability of macrophages to accumulate lipid.…”

Pleiotropic effects of niacin: Current possibilities for its clinical use

“…These effects certainly warrant comprehensive evaluation, especially given the criticism leveled at the methodological flaws contained in the published results of the AIM-HIGH and HPS2-THRIVE studies (18)(19)(20)(21)(22)(23). Indeed, both of these studies have serious drawbacks (see above): the AIM-HIGH study was underpowered, low-dose niacin was administered to patients in the placebo-group (18) and it suffered from selection bias (patients with triacylglycerols above 400 mg per 100 mL were excluded) (20).…”

“…The design of both studies ignored the pharmacokinetics of ER niacin (meal time vs. bedtime dosages) (17,20). The AIM-HIGH study was terminated prematurely; and the combination of niacin with laropiprant, a prostaglandin-D2 receptor antagonist, did not account for the adverse effects of laropiprant when administered exclusively (immune dysfunction, gastrointestinal bleeding, attenuation of reverse cholesterol transport) (21).…”