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.
Copyright 2000 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / pharmacology*
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Animals
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Calcimycin / pharmacology
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Cell Division / drug effects
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Cells, Cultured
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Dinoprost / pharmacology
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Enzyme Activation
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / drug effects
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ErbB Receptors / physiology*
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
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Inositol 1,4,5-Trisphosphate / metabolism
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Liver / cytology
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Liver / drug effects*
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Liver / metabolism
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Male
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Norepinephrine / pharmacology
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Pertussis Toxin*
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Phosphatidylinositol Diacylglycerol-Lyase
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Phosphoinositide Phospholipase C
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Phospholipase D / metabolism
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Rats
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Rats, Wistar
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Receptors, Adrenergic, alpha-1 / physiology
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Thapsigargin / pharmacology
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Type C Phospholipases / metabolism
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Vasopressins / pharmacology*
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Virulence Factors, Bordetella / pharmacology*
Substances
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Receptors, Adrenergic, alpha-1
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Virulence Factors, Bordetella
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Vasopressins
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Angiotensin II
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Calcimycin
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Epidermal Growth Factor
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Thapsigargin
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Inositol 1,4,5-Trisphosphate
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Dinoprost
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Pertussis Toxin
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ErbB Receptors
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Type C Phospholipases
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Phosphoinositide Phospholipase C
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Phospholipase D
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GTP-Binding Protein alpha Subunits, Gi-Go
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Phosphatidylinositol Diacylglycerol-Lyase
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Norepinephrine