title: Reduction of ryanodine binding and cytosolic Ca2+ levels in liver by the immunosuppressant FK506.
abstract: The mechanism of action of the immunosuppressant FK506 in the liver was studied. The hypothesis was tested that FK506 exerts its effect in the liver by interacting with the ryanodine-binding Ca2+ release channel. Two types of experiments were carried out: (1) [3H]-ryanodine binding studies with isolated microsomal fractions, and (2) cytosolic-free Ca2+ ([Ca2+]i) measurements with the intracellular Ca(2+)-indicator fura-2. The inclusion of FK506 in the incubation medium significantly decreased the binding of [3H]-ryanodine to liver microsomes. The Bmax of binding in control experiments was 405 fmol/mg protein; the presence of FK506 decreased the Bmax to 157 fmol/mg protein. Measurements of [Ca2+]i in the presence and absence of FK506 showed a decrease in [Ca2+]i in the presence of FK506. The data support the notion that FK506 interacts with the ryanodine binding Ca2+ channel in the liver and suggest a critical role for the ryanodine-binding Ca2+ channel in the hepatic responses to FK506. The interaction between FKBP-12 (FK506 binding protein) and the ryanodine-binding Ca2+ channel may be an essential link in the chain of events by which FK506 alters Ca(2+)-dependent cellular processes.
authors.affiliation: Department of Physiology and Cell Biology, University of Texas Medical School at Houston 77225.
authors.forename: N
authors.initials: N
authors.lastname: Kraus-Friedmann
authors.forename: L
authors.initials: L
authors.lastname: Feng
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000032:analysis*; D015220:Calcium Channels / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D012433:Ryanodine; D002118:Calcium; D016559:Tacrolimus