Cyclic AMP Acts Through Rap1 and JNK Signaling to Increase Expression of Cutaneous Smooth Muscle alpha2C-Adrenoceptors

Details

• Personal Author:
  Chotani MA ; Eid AH ; Flavahan NA ; Miller TJ ; Mitra S
• Description:
  Cold increases cutaneous vasoconstriction by unmasking the contractile activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) in vascular smooth muscle cells (VSMCs), which is mediated by the cold-induced mobilization of alpha(2C)-ARs from the transGolgi to the cell surface. The expression of alpha(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 muM), the selective EPAC activator, 8-pCPT-2'-O-Me-cyclic AMP (CMC; 100 microM), or a constitutively active mutant of Rap1 (Rap1CA) increased the activity of c-Jun NH(2)-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 microM). Rap1CA increased the activity of an alpha(2C)-AR promoter-reporter construct, which was inhibited by SP600125 (3 microM) or by the mutation of an AP-1 binding site in the alpha(2C)-AR promoter. Furthermore, forskolin (10 microM) or CMC (100 microM) increased the expression of the alpha(2C)-AR protein, and these effects were inhibited by SP600125 (3 microM). Therefore, cyclic AMP increases the expression of alpha(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 alpha(2C)-AR gene. By increasing the expression of cold-responsive alpha(2C)-ARs, this pathway may contribute to enhanced cold-induced vasoconstriction in the cutaneous circulation, including Raynaud's phenomenon. [Description provided by NIOSH]
• Subjects:
  Automation Coal Coal Mining Mining Occupational Health Safety
• Keywords:
  Blood-vessels Cell-biology Cell-differentiation Cell-function Cell-transformation Enzymes Genes Hormone-activity Hormones Muscle-cells Proteins Vasoactive-agents

  More +
• ISSN:
  0363-6135
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; Ohio ; OSHA Region 3 ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  295
• Issue:
  1
• NIOSHTIC Number:
  nn:20034384
• Citation:
  Am J Physiol Heart Circ Physiol 2008 Jul; 295(1):H266-H272
• Contact Point Address:
  N. A. Flavahan, Dept. of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Ross Research Bldg., R 370/372, 720 Rutland Ave., Baltimore, MD 21205
• Email:
  nflavah1@jhmi.edu
• Federal Fiscal Year:
  2008
• Performing Organization:
  Jonhs Hopkins University
• Peer Reviewed:
  True
• Start Date:
  20050801
• Source Full Name:
  American Journal of Physiology - Heart and Circulatory Physiology
• End Date:
  20100731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4940dd9fa42f8ad94077257aec5519a4a8abb6b6efb97eaa08d07ae83addda1430a9d7a102764d9345102a92f868a03935ba8dc2de4daf53599966f6b9b6d68f
• Download URL:
  https://stacks.cdc.gov/view/cdc/189610/cdc_189610_DS1.pdf
• File Type:
  [PDF - 695.69 KB ]