Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 356, Issue 2, Pages 456-465Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.115.229146
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Funding
- Department of Pharmacology and Toxicology at the Brody School of Medicine, East Carolina University
- Zagazig Faculty of Pharmacy via Egyptian Government (Scholarship Missions Program, Ministry of Higher Education)
- National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [2R01-AA01444-09]
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G protein-coupled receptor 109A (GPR109A) activation by its ligand nicotinic acid (NA) in immune cells increases Ca2+ levels, and Ca2+ induces glutamate release and oxidative stress in central blood pressure (BP)-regulating nuclei, for example, the rostral ventrolateral medulla (RVLM), leading to sympathoexcitation. Despite NA's ability to reach the brain, the expression and function of its receptor GPR109A in the RVLM remain unknown. We hypothesized that NA activation of RVLM GPR109A causes Ca2+-dependent L-glutamate release and subsequently increases neuronal oxidative stress, sympathetic activity, and BP. To test this hypothesis, we adopted a multilevel approach, which included pharmacologic in vivo studies along with ex vivo and in vitro molecular studies in rat pheochromocytoma cell line (PC12) cells (which exhibit neuronal phenotype). We present the first evidence for GPR109A expression in the RVLM and in PC12 cells. Next, we showed that RVLM GPR109A activation (NA) caused pressor and bradycardic responses in conscious rats. The resemblance of these responses to those caused by intra-RVLM glutamate and their attenuation by NMDA receptor (NMDAR) blockade (2-amino-5-phosphonopentanoic acid) and enhancement by L-glutamate uptake inhibition (L-trans-pyrrolidine-2,4- dicarboxylic acid, PDC) supported our hypothesis. NA increased Ca2+, glutamate, nitric oxide and reactive oxygen species (ROS) levels in PC12 cells and increased RVLM ROS levels. The inactive NA analog isonicotinic acid failed to replicate the cardiovascular and biochemical effects of NA. Further, GPR109A knockdown (siRNA) abrogated the biochemical effects of NA in PC12 cells. These novel findings yield new insight into the role of RVLM GPR109A in central BP control.
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