Abstract
Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cells, Cultured
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Constitutive Androstane Receptor
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Epidermal Growth Factor / metabolism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / chemistry
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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GABA Modulators / metabolism
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GABA Modulators / pharmacology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Male
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Mice
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Mice, Inbred C3H
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Models, Molecular
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Phenobarbital / metabolism
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Phenobarbital / pharmacology*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Phosphatase 2 / genetics
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Protein Phosphatase 2 / metabolism
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Protein Structure, Tertiary
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RNA Interference
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Receptors for Activated C Kinase
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction / drug effects*
Substances
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Constitutive Androstane Receptor
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GABA Modulators
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Receptors for Activated C Kinase
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Receptors, Cell Surface
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Receptors, Cytoplasmic and Nuclear
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Epidermal Growth Factor
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ErbB Receptors
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Protein Phosphatase 2
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Phenobarbital