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Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

Abstract

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not  More>>
Authors:
Tang, Yuting; [1]  Zhou, Lubing; [1]  Gunnet, Joseph W; [1]  Wines, Pamela G; [1]  Cryan, Ellen V; [1]  Demarest, Keith T [1] 
  1. Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States)
Publication Date:
Jun 23, 2006
Product Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 345; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2006.04.051; PII: S0006-291X(06)00872-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; ARACHIDONIC ACID; BRADYKININ; CALCIUM IONS; GENES; GTP-ASES; LIPIDS; LUCIFERASE; METABOLISM; NICOTINIC ACID; PHOSPHOTRANSFERASES; PROSTAGLANDINS; RECEPTORS; SIDE EFFECTS; SKIN; STIMULATION; THERAPY; TOXINS
OSTI ID:
20854305
Country of Origin:
United States
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0006-291X; BBRCA9; TRN: US07R0080027295
Submitting Site:
INIS
Size:
page(s) 29-37
Announcement Date:
Apr 18, 2007

Citation Formats

Tang, Yuting, Zhou, Lubing, Gunnet, Joseph W, Wines, Pamela G, Cryan, Ellen V, and Demarest, Keith T. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.04.051.
Tang, Yuting, Zhou, Lubing, Gunnet, Joseph W, Wines, Pamela G, Cryan, Ellen V, & Demarest, Keith T. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A. United States. doi:10.1016/j.bbrc.2006.04.051.
Tang, Yuting, Zhou, Lubing, Gunnet, Joseph W, Wines, Pamela G, Cryan, Ellen V, and Demarest, Keith T. 2006. "Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A." United States. doi:10.1016/j.bbrc.2006.04.051. https://www.osti.gov/servlets/purl/10.1016/j.bbrc.2006.04.051.
@misc{etde_20854305,
title = {Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A}
author = {Tang, Yuting, Zhou, Lubing, Gunnet, Joseph W, Wines, Pamela G, Cryan, Ellen V, and Demarest, Keith T}
abstractNote = {HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.}
doi = {10.1016/j.bbrc.2006.04.051}
journal = {Biochemical and Biophysical Research Communications}
issue = {1}
volume = {345}
place = {United States}
year = {2006}
month = {Jun}
}