Abstract
Ligand-gated ion channel subunits show a striking abundance of highly conserved proline residues. We, therefore, tested the hypothesis that peptidyl-prolyl isomerases may be involved in the maturation of these channels. Cyclosporin A, a selective blocker of a ubiquitous isomerase cyclophilin, reduced the surface expression in Xenopus oocytes of functional homo-oligomeric receptors containing nicotinic acetylcholine receptor subunit alpha 7 without blocking alpha 7 polypeptide synthesis. This effect could be generalized to the homo-oligomeric 5-hydroxytryptamine type 3 receptor but not to the hetero-oligomeric muscle nicotinic receptor. An alpha 7 receptor could be rescued from cyclosporin A blockade by coexpressed muscle non-alpha subunits. The effect of cyclosporin A was reversed by overexpression of exogenous rat brain cyclophilin. These findings indicate that cyclophilins may play a critical role in the maturation of homo-oligomeric receptors, acting directly or indirectly as prolyl isomerases or as molecular chaperones.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Isomerases / biosynthesis
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Amino Acid Isomerases / metabolism*
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Animals
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Blotting, Western
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Brain / metabolism*
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Bungarotoxins / metabolism
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Calcimycin / pharmacology
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Carrier Proteins / biosynthesis
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Carrier Proteins / metabolism*
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Cloning, Molecular
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Cyclosporine / pharmacology
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DNA, Complementary / metabolism
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Electrophoresis, Polyacrylamide Gel
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Female
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Gene Expression
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Ion Channels / biosynthesis*
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Ion Channels / drug effects
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Ion Channels / isolation & purification
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Luciferases / biosynthesis
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Luciferases / metabolism
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Membrane Potentials / drug effects
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Muscles / metabolism
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Oocytes / drug effects
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Oocytes / physiology
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Peptidylprolyl Isomerase
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Rats
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Receptors, Serotonin / biosynthesis*
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Receptors, Serotonin / drug effects
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Tacrolimus / pharmacology
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Xenopus laevis
Substances
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Bungarotoxins
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Carrier Proteins
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DNA, Complementary
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Ion Channels
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Receptors, Serotonin
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Calcimycin
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Cyclosporine
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Luciferases
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Amino Acid Isomerases
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Peptidylprolyl Isomerase
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Tacrolimus