Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252331
Title: Stimulation of the mitogen-activated protein kinase (MAPK) pathway in DDT₁MF-2 cells by adenosine A₁ receptors and histamine H₁ receptors
Author: Robinson, Alexander John
ISNI:       0000 0001 3527 1802
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2002
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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/₁₁coupled) 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/₀ proteins, PI-3K, and MEKl, but appeared to be independent of tyrosine kinase activation. H₁R-mediated ERK 1/2 in DDT₁MF-2 cells involved PI-3K, tyrosine kinases, PKC, MEKl, and, unexpectedly, Gᵢ/₀ 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/₀ proteins. However, neither the A₁R nor the H₁R activated the JNK/SAPK cascade in DDT,MF-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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.252331  DOI: Not available
Keywords: Smooth muscle
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