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Adenylate cyclase, cyclic AMP and extracellular-signal-regulated kinase-2 in airway smooth muscle - modulation by protein kinase C and growth serum

Moughal, N and Stevens, P A and Kong, D and Pyne, S and Pyne, N J (1995) Adenylate cyclase, cyclic AMP and extracellular-signal-regulated kinase-2 in airway smooth muscle - modulation by protein kinase C and growth serum. Biochemical journal, 306 (3). pp. 723-726. ISSN 0264-6021

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Abstract

Bradykinin and phorbol 12-myristate 13-acetate stimulate adenylate cyclase activity in serum-depleted cultured airway smooth muscle via a protein kinase C (PKC)-dependent pathway. The probable target is the type II adenylate cyclase, which can integrate coincident signals from both PKC and Gs. Therefore, activation of Gs (by cholera-toxin pre-treatment) amplified the bradykinin-stimulated cyclic AMP signal and concurrently attenuated the partial activation of extracellular-signal-regulated kinase-2 (ERK-2) by bradykinin. We have previously demonstrated that, in order to induce full activation of ERK-2 with bradykinin, it is necessary to obliterate PKC-stimulated cyclic AMP formation. We concluded that the cyclic AMP signal limits the magnitude of ERK-2 activation [Pyne, Moughal, Stevens, Tolan and Pyne (1994) Biochem. J. 304, 611-616]. The present study indicates that the bradykinin-stimulated ERK-2 pathway is entirely cyclic AMP-sensitive, and suggests that coincident signal detection by adenylate cyclase may be an important physiological route for the modulation of early mitogenic signalling. Furthermore, the direct inhibition of adenylate cyclase activity enables bradykinin to induce DNA synthesis, indicating that the PKC-dependent activation of adenylate cyclase limits entry of cells into the cell cycle. These studies suggest that the mitogenicity of an agonist may be governed, in part, by its ability to stimulate an inhibitory cyclic AMP signal pathway in the cell. The activation of adenylate cyclase by PKC appears to be downstream of phospholipase D. However, in cells that were maintained in growth serum (i.e. were not growth-arrested), bradykinin was unable to elicit a PKC-stimulated cyclic AMP response. The lesion in the signal-response coupling was not at the level of either the receptor or phospholipase D, which remain functionally operative and suggests modification occurs at either PKC or adenylate cyclase itself. These studies are discussed with respect to the cell signal regulation of mitogenesis in airway smooth muscle.

Item type: Article
ID code: 34923
Keywords: adenylate cyclase, animals, bradykinin, calcium-calmodulin-dependent protein kinases, cell cycle, cells, cultured, culture media, cyclic AMP, guinea pigs, mitogen-activated protein kinase 1, muscle, smooth, protein kinase C, second messenger systems, signal transduction, phospholipase-D, RAF , cells, inhibition, activation, stimulation, Pharmacy and materia medica, Biochemistry, Cell Biology, Molecular Biology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Pure Administrator
    Date Deposited: 15 Nov 2011 05:18
    Last modified: 05 Sep 2014 12:33
    URI: http://strathprints.strath.ac.uk/id/eprint/34923

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