Peptidyl prolyl cis-trans isomerase activity of cyclophilin A in functional homo-oligomeric receptor expression

The functional expression of homo-oligomeric alpha 7 neuronal nicotinic and type 3 serotonin receptors is dependent on the activity of a cyclophilin, In this paper we demonstrate that the mechanism of cyclophilin action during functional homo-oligomeric receptor expression in Xenopus oocytes is distinct from the calcineurin-dependent immunosuppressive mechanism by showing that a nonimmunosuppressive analog of cyclosporin A (CsA), SDZ 211-811, reduces functional receptor expression to the same extent as CsA, The cytoplasmic subtype of cyclophilin, cyclophilin A (CyPA), appears to be required for functional receptor expression, This is because overexpression of CyPA and a CyPA mutant that is deficient in CsA binding activity reverses CsA induced reduction in functional receptor expression, The mechanism of action of CyPA is likely to involve its prolyl isomerase activity because a mutant CyPA with a single amino acid substitution (arginine 55 to alanine) that is predicted to produce a 1000-fold attenuation in isomerase activity fails to reverse the cyclosporin A effect, Our data also suggest that CyPA does not form a stable complex with receptor subunits.