Noradrenaline-induced paxillin phosphorylation, ERK activation and MEK-regulated contraction in intact rat mesenteric arteries.
In rat mesenteric arteries, noradrenaline (NA) induces a time-dependent increase in tyrosine phosphorylation of a number of proteins, one of which was identified as paxillin. NA-induced protein tyrosine phosphorylation was ablated by tyrosine kinase inhibition, virtually unaffected by protein kinase C (PKC) inhibition or PKC downregulation and was mimicked by KCl. NA also caused a time-dependent activation of the extracellular signal-regulated kinases (ERK)1 and ERK2. These responses were blocked by the ERK-activating kinase (MEK) inhibitor PD98059 and by tyrosine kinase inhibition but only modestly attenuated by PKC downregulation or inhibition. Pretreatment of cannulated mesenteric arteries (50 mm Hg internal pressure) with PD98059 significantly reduced the contractile responsiveness of the vessels to NA (1.56 +/- 0.14 microM, EC(50) control; 3.32 +/- 0.49 microM, EC(50) + PD98059, p < 0.01). Thus, NA induces time-dependent increases in protein-tyrosine phosphorylation and ERK activation in rat mesenteric arteries that could suggest a role for Ca(2+)-dependent non-receptor tyrosine kinases and ERKs in the response of small arteries to NA. In addition, the modulation of NA-induced mesenteric artery contraction by inhibition of the MEK/ERK pathway further implicates ERK in the regulation of, though perhaps not the mediation of NA-induced small artery contraction.
Ward
Donald T
DT
School of Biological Sciences, University of Manchester, Manchester, UK.
Alder
Angela C
AC
Ohanian
Jacqueline
J
Ohanian
Vasken
V
D000818:Animals; D002118:Calcium / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D051419:Paxillin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051419:Paxillin; D010750:Phosphoproteins; C496063:Pxn protein, rat; D015240:Phorbol 12,13-Dibutyrate; D011189:Potassium Chloride; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium; D009638:Norepinephrine