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Research ArticleCardiovascular

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

Samar Rezq and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 456-465; DOI: https://doi.org/10.1124/jpet.115.229146
Samar Rezq
Department of Pharmacology, School of Medicine, East Carolina University, North Carolina
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Abdel A. Abdel-Rahman
Department of Pharmacology, School of Medicine, East Carolina University, North Carolina
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Abstract

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.

Footnotes

    • Received September 3, 2015.
    • Accepted November 2, 2015.
  • This research was supported by the Department of Pharmacology and Toxicology at the Brody School of Medicine, East Carolina University; and in part by the Zagazig Faculty of Pharmacy via a scholarship provided by the Egyptian Government (Scholarship Missions Program, Ministry of Higher Education); and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant 2R01-AA01444-09].

  • dx.doi.org/10.1124/jpet.229146.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
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Research ArticleCardiovascular

RVLM GPR109A Mediates Glutamate-Dependent Pressor Response

Samar Rezq and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 456-465; DOI: https://doi.org/10.1124/jpet.115.229146

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Research ArticleCardiovascular

RVLM GPR109A Mediates Glutamate-Dependent Pressor Response

Samar Rezq and Abdel A. Abdel-Rahman
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 456-465; DOI: https://doi.org/10.1124/jpet.115.229146
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