Effects of pertussis toxin on extracellular signal-regulated kinase activation in hepatocytes by hormones and receptor-independent agents: evidence suggesting a stimulatory role of G(i) proteins at a level distal to receptor coupling

J Cell Physiol. 2000 Jul;184(1):27-36. doi: 10.1002/(SICI)1097-4652(200007)184:1<27::AID-JCP3>3.0.CO;2-Q.

Abstract

It was previously found that pertussis toxin (PTX) pretreatment inhibits the activation of extracellular signal-regulated kinases ERK1 (p44(mapk)) and ERK2 (p42(mapk)) in hepatocytes in response to either agonists that bind to heptahelical receptors or epidermal growth factor (EGF), suggesting a role of G(i) proteins in stimulatory mechanisms for ERK1/2. The present work shows that ERK1/2 is activated in a PTX-sensitive way not only by vasopressin, angiotensin II, prostaglandin (PG) F(2alpha), alpha(1)-adrenergic stimulation, and EGF but also by agents whose actions bypass receptors and stimulate protein kinase C (PKC) and/or elevate intracellular Ca(2+), such as 12-O-tetradecanoyl phorbol-13-acetate (TPA), exogenous phosphatidylcholine-specific phospholipase C (PC-PLC, from Bacillus cereus), thapsigargin, and the Ca(2+) ionophore A23187. Under the same conditions, PTX did not affect agonist stimulation of phosphoinositide-specific phospholipase C (PI-PLC) (IP(3) generation), and did not reduce the activation by these agents of phospholipase D (PLD). The results suggest that in hepatocytes a PTX-sensitive mechanism, presumably involving G(i) proteins, exerts a stimulatory effect on ERK at a level distal to receptor coupling, acting either as an integral part of the signaling pathway(s) or by a permissive, synergistic regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Calcimycin / pharmacology
  • Cell Division / drug effects
  • Cells, Cultured
  • Dinoprost / pharmacology
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / drug effects
  • ErbB Receptors / physiology*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Liver / cytology
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Norepinephrine / pharmacology
  • Pertussis Toxin*
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Phosphoinositide Phospholipase C
  • Phospholipase D / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / physiology
  • Thapsigargin / pharmacology
  • Type C Phospholipases / metabolism
  • Vasopressins / pharmacology*
  • Virulence Factors, Bordetella / pharmacology*

Substances

  • Receptors, Adrenergic, alpha-1
  • Virulence Factors, Bordetella
  • Vasopressins
  • Angiotensin II
  • Calcimycin
  • Epidermal Growth Factor
  • Thapsigargin
  • Inositol 1,4,5-Trisphosphate
  • Dinoprost
  • Pertussis Toxin
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • Phosphoinositide Phospholipase C
  • Phospholipase D
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Norepinephrine