Prolyl isomerase requirement for the expression of functional homo-oligomeric ligand-gated ion channels.
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.
Helekar
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SA
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030.
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Neff
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Patrick
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D000591:Amino Acid Isomerases / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002038:Bungarotoxins / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D003001:Cloning, Molecular; D016572:Cyclosporine / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015870:Gene Expression; D007473:Ion Channels / Q000096:biosynthesis* / Q000187:drug effects / Q000302:isolation & purification; D008156:Luciferases / Q000096:biosynthesis / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009132:Muscles / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D019696:Peptidylprolyl Isomerase; D051381:Rats; D011985:Receptors, Serotonin / Q000096:biosynthesis* / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology; D014982:Xenopus laevis
D002038:Bungarotoxins; D002352:Carrier Proteins; D018076:DNA, Complementary; D007473:Ion Channels; D011985:Receptors, Serotonin; D000001:Calcimycin; D016572:Cyclosporine; D008156:Luciferases; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus