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Robinson, AJ, 2002. Stimulation of the mitogen-activated protein kinase (MAPK) pathway in DDT1MF-2 cells by adenosine A1 receptors and histamine H1 receptors. PhD, Nottingham Trent University.
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Abstract
The mitogen-activated protein kinases (MAPKs) are a group of serine/threonine protein kinases comprising of three main subfamilies. Extracellular signal-regulated kinases (ERKs 1/2, or p42/p44 MAPKs) are primarily associated with the regulation of cell proliferation and differentiation, whereas the c-jun N-terminal kinases (JNKs/SAPKs) and p38 MAPKs are involved in apoptosis, inflammation, and responses to environmental stress. Adenosine A1 receptors (A1Rs; Gi/o-coupled) have been implicated in cardiac and neuronal protection, and histamine H1 receptors (H1Rs; Gq/11- coupled) mediate various physiological effects, such as vascular smooth muscle contraction. In this study the coupling of these two G protein-coupled receptors (GPCRs) to the three main MAPK cascades, and the possible physiological consequences, were investigated in the smooth muscle cell line DDT1MF-2.
Both A1Rs and H1Rs mediated ERK 1/2 activation in DDT1MF-2 cells. ERK 1/2 stimulation by A1Rs involved Gi/o proteins, PI-3K, and MEK1, but appeared to be independent of tyrosine kinase activation. H1R-mediated ERK 1/2 in DDT1MF-2 cells involved PI-3K, tyrosine kinases, PKC, MEK1, and, unexpectedly, Gi/o proteins. A1Rs and H1Rs also mediated p38 MAPK activation in DDT1MF-2 cells. Similar to ERK 1/2 activation, p38 MAPK activation by both A1Rs and H1Rs involved Gi/o proteins. However, neither the A1R nor the H1R activated the JNK/SAPK cascade in DDT1MF-2 cells.
Both A1R and H1R stimulation had no significant effect on DDT1MF-2 cell proliferation, and did not potentiate EGF-induced DDT1MF-2 cell growth. A1R stimulation also had no significant effect on FCS-mediated DDT1MF-2 cell proliferation. A1Rs and H1Rs had no significant effect on both staurosporine-and hydrogen peroxide-induced cell death. Also, both receptors had no significant effect on staurosporine-induced caspase-3 activation. For comparison, EGF did significantly reduce staurosporine-induced caspase- 3 activation.
In conclusion, this study has shown that A1Rs and H1Rs couple to the p42/p44 MAPK and p38 MAPK cascades in DDT1MF-2 cells. Since neither receptor induced or potentiated DDT1MF-2 cell proliferation, or inhibited caspase-3 activation, further experiments are required in order to establish the physiological roles of A1Rs and H1Rs in DDT1MF-2 cells.
| Item Type: | Thesis |
|---|---|
| Creators: | Robinson, A.J. |
| Date: | 2002 |
| ISBN: | 9781369314250 |
| Identifiers: | Number Type PQ10183149 Other |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Linda Sullivan |
| Date Added: | 18 Sep 2020 09:20 |
| Last Modified: | 26 Jul 2023 11:03 |
| URI: | https://irep.ntu.ac.uk/id/eprint/40796 |
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