Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase

J Biol Chem. 1996 Jun 14;271(24):14169-75. doi: 10.1074/jbc.271.24.14169.

Abstract

In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a rapid increase in mitogen-activated protein kinase (MAPK) activity through the Ang II type 1 receptor, which was insensitive to pertussis toxin but was abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK activation was not affected by the protein kinase C inhibitor, GF109203X, and was only partially impaired by pretreatment with a phorbol ester, whereas both treatments completely prevented MAPK activation by the phorbol ester. Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor, genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+ ionophore A23187. Ang II caused a rapid increase in the binding of GTP to p21(ras), and this was inhibited by genistein, TMB-8, and calmidazolium but not by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK activation through the Ang II type 1 receptor could be mediated by p21(ras)activation through a currently unidentified tyrosine kinase that lies downstream of Gq-coupled Ca2+/calmodulin signals.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Angiotensin II / pharmacology*
  • Animals
  • Aorta, Thoracic
  • Calcimycin / pharmacology
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Estrenes / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Gallic Acid / analogs & derivatives
  • Gallic Acid / pharmacology
  • Genistein
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Isoflavones / pharmacology
  • Kinetics
  • Maleimides / pharmacology
  • Molecular Sequence Data
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / physiology*
  • Peptides / chemical synthesis
  • Peptides / metabolism
  • Pertussis Toxin
  • Protein Kinase C / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Pyrrolidinones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Substrate Specificity
  • Type C Phospholipases / antagonists & inhibitors
  • Virulence Factors, Bordetella / pharmacology

Substances

  • Enzyme Inhibitors
  • Estrenes
  • Imidazoles
  • Indoles
  • Isoflavones
  • Maleimides
  • Peptides
  • Pyrrolidinones
  • Virulence Factors, Bordetella
  • Angiotensin II
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Calcimycin
  • calmidazolium
  • 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate
  • Gallic Acid
  • Adenosine Triphosphate
  • Genistein
  • Pertussis Toxin
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Type C Phospholipases
  • GTP-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)
  • bisindolylmaleimide I
  • Calcium