Document Detail

Nicotinic acid receptor agonists differentially activate downstream effectors.
MedLine Citation:
PMID:  17452318     Owner:  NLM     Status:  MEDLINE    
Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a Gi protein-coupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.
Jeremy G Richman; Martha Kanemitsu-Parks; Ibragim Gaidarov; Jill S Cameron; Peter Griffin; Hong Zheng; Nuvia C Guerra; Linda Cham; Dominique Maciejewski-Lenoir; Dominic P Behan; Doug Boatman; Ruoping Chen; Philip Skinner; Pricilla Ornelas; M Gerard Waters; Samuel D Wright; Graeme Semple; Daniel T Connolly
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Publication Detail:
Type:  Journal Article     Date:  2007-04-23
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-06-18     Completed Date:  2007-08-23     Revised Date:  2011-11-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18028-36     Citation Subset:  IM    
Arena Pharmaceuticals, Inc., San Diego, California 92121, USA.
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MeSH Terms
Adipose Tissue / metabolism
CHO Cells
COS Cells
Cercopithecus aethiops
Gene Expression Regulation*
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Models, Chemical
Nicotinic Agonists / metabolism*
Prostaglandin D2 / metabolism
Receptors, G-Protein-Coupled / chemistry,  metabolism*
Receptors, Nicotinic / chemistry,  metabolism*
Reg. No./Substance:
0/Hcar2 protein, mouse; 0/Nicotinic Agonists; 0/Receptors, G-Protein-Coupled; 0/Receptors, Nicotinic; 41598-07-6/Prostaglandin D2; EC Protein Kinase 1; EC Protein Kinase 3

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