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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H266    most recent 00084.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Eid, A. H. Articles by Flavahan, N. A. Search for Related Content PubMed PubMed Citation Articles by Eid, A. H. Articles by Flavahan, N. A.

Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle _2C-adrenoceptors

¹Lebanese International University and University of Balamand, Beirut, Lebanon; ²Davis Heart and Lung Research Institute, Ohio State University, Columbus, Ohio; and ³Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland

Submitted 25 January 2008 ; accepted in final form 13 May 2008

Cold increases cutaneous vasoconstriction by unmasking the contractile activity of _2C-adrenoceptors (_2C-ARs) in vascular smooth muscle cells (VSMCs), which is mediated by the cold-induced mobilization of _2C-ARs from the transGolgi to the cell surface. The expression of _2C-ARs in human cutaneous VSMCs is under dual regulation by cyclic AMP: gene transcription is inhibited by cyclic AMP acting through protein kinase A but is increased by cyclic AMP acting through the exchange protein directly activated by cyclic AMP (EPAC) and the GTP-binding protein Rap1. Experiments were performed to further characterize the Rap1 signaling pathway. Forskolin (10 µM), the selective EPAC activator, 8-pCPT-2'-O-Me-cyclic AMP (CMC; 100 µM), or a constitutively active mutant of Rap1 (Rap1CA) increased the activity of c-Jun NH₂-terminal kinase (JNK) in human cutaneous VSMCs. This was associated with the increased phosphorylation of c-Jun and activation of an activator protein (AP)-1 reporter construct, which were inhibited by the JNK inhibitor SP600125 (3 µM). Rap1CA increased the activity of an _2C-AR promoter-reporter construct, which was inhibited by SP600125 (3 µM) or by the mutation of an AP-1 binding site in the _2C-AR promoter. Furthermore, forskolin (10 µM) or CMC (100 µM) increased the expression of the _2C-AR protein, and these effects were inhibited by SP600125 (3 µM). Therefore, cyclic AMP increases the expression of _2C-ARs in cutaneous VSMCs by activating a novel Rap1 signaling pathway, mediated by the activation of JNK, AP-1, and the subsequent transcriptional activation of the _2C-AR gene. By increasing the expression of cold-responsive _2C-ARs, this pathway may contribute to enhanced cold-induced vasoconstriction in the cutaneous circulation, including Raynaud's phenomenon.

Raynaud's phenomenon; activator protein-1; c-Jun NH₂-terminal kinase; transcription; adenosine 5'-monophosphate