Document Detail

Regulation of p42/p44 MAPK and p38 MAPK by the adenosine A(1) receptor in DDT(1)MF-2 cells.
MedLine Citation:
PMID:  11226388     Owner:  NLM     Status:  MEDLINE    
The mitogen-activated protein kinase (MAPK) family consists of the p42/p44 MAPKs and the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38 MAPK. We have previously reported that the human adenosine A(1) receptor stimulates p42/p44 MAPK in transfected Chinese hamster ovary cells. In this study, we have investigated whether the endogenous adenosine A(1) receptor in the smooth muscle cell line, DDT(1)MF-2 activates p42/p44 MAPK, JNK and p38 MAPK. The adenosine A(1) receptor agonist N(6)-cyclopentyladenosine stimulated time and concentration-dependent increases in p42/p44 MAPK and p38 MAPK phosphorylation in DDT(1)MF-2 cells. No increases in JNK phosphorylation were observed following adenosine A(1) receptor activation. N(6)-cyclopentyladenosine-mediated increases in p42/p44 MAPK and p38 MAPK phosphorylation were blocked by the selective adenosine A(1) receptor antagonist 1,3-dipropylcyclopentylxanthine and following pretreatment of cells with pertussis toxin. Furthermore, adenosine A(1) receptor-mediated increases in p42/p44 MAPK were sensitive to the MAPK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), whereas p38 MAPK responses were blocked by the p38 MAPK inhibitor SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). The broad range protein tyrosine kinase inhibitors genistein and tyrphostin A47 (alpha-cyano-(3,4-dihydroxy)thiocinnamide) did not block adenosine A(1) receptor stimulation of p42/p44 MAPK. For comparison, insulin-mediated increases in p42/p44 MAPK were blocked by genistein and tyrphostin A47. The Src tyrosine kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the epidermal growth factor receptor tyrosine kinase inhibitor AG1478 (4-(3-chloroanilino)-6,7-dimethoxyquinazoline) also had no effect on adenosine A(1) receptor stimulation of p42/p44 MAPK. Furthermore, the protein kinase C inhibitors Ro 31-8220 (3-[1-[3-(2-isothioureido) propyl]indol-3-yl]-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dione), chelerythrine and GF 109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) were without effect on adenosine A(1) receptor-induced p42/p44 MAPK phosphorylation. In contrast, wortmannin and LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), inhibitors of phosphatidylinositol 3-kinase, attenuated adenosine A(1) receptor stimulation of p42/p44 MAPK phosphorylation. In conclusion, the adenosine A(1) receptor stimulates p42/p44 MAPK through a pathway which appears to be independent of tyrosine kinase activation but involves phosphatidylinositol 3-kinase. Finally, adenosine A(1) receptor stimulation in DDT(1)MF-2 cells also activated p38 MAPK but not JNK via a pertussis toxin-sensitive pathway.
A J Robinson; J M Dickenson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of pharmacology     Volume:  413     ISSN:  0014-2999     ISO Abbreviation:  Eur. J. Pharmacol.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-03-06     Completed Date:  2001-05-31     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  1254354     Medline TA:  Eur J Pharmacol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  151-61     Citation Subset:  IM    
Department of Life Sciences, Faculty of Science and Mathematics, Nottingham Trent University, Clifton Lane, NG11 8NS, Nottingham, UK
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / drug effects,  metabolism
Adenosine / analogs & derivatives,  pharmacology
Cell Line
Enzyme Inhibitors / pharmacology
Hypoglycemic Agents / pharmacology
Insulin / pharmacology
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1 / drug effects,  metabolism*
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases / drug effects,  metabolism*
Muscle, Smooth / cytology,  drug effects,  metabolism*
Protein Kinase C / drug effects,  metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors
Receptors, Purinergic P1 / drug effects,  metabolism*
Signal Transduction / drug effects,  physiology
Vasodilator Agents / pharmacology
Xanthines / pharmacology
p38 Mitogen-Activated Protein Kinases
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Hypoglycemic Agents; 0/Receptors, Purinergic P1; 0/Vasodilator Agents; 0/Xanthines; 102146-07-6/1,3-dipropyl-8-cyclopentylxanthine; 11061-68-0/Insulin; 41552-82-3/N(6)-cyclopentyladenosine; 58-61-7/Adenosine; EC 3-Kinase; EC Kinases; EC Kinase C; EC Mitogen-Activated Protein Kinases; EC Protein Kinase 1; EC Protein Kinase 3; EC Protein Kinases; EC Mitogen-Activated Protein Kinases

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