High brain densities of the immunophilin FKBP colocalized with calcineurin

Abstract

The immunophilins cyclophilin and FK506 binding protein (FKBP) are small, predominantly soluble proteins that bind the immunosuppressant drugs cyclosporin A and FK506, respectively, with high affinity, and which seem to mediate their pharmacological actions. The Ca(2+)-dependent protein phosphatase, calcineurin, binds the cyclophilin-cyclosporin A and FKBP-FK506 complexes, indicating that calcineurin might mediate the actions of these drugs. A physiological role for the immunophilins in the nervous system is implied by a close homology between the structure of NINA A, a protein in the neural retina of Drosophila, and cyclophilin, as well as by the high density of FKBP messenger RNA in brain tissue. Here we report that the levels of FKBP and mRNA in rat brain are extraordinarily high and that their regional localization is virtually identical to that of calcineurin, indicating that there may be a physiological link between calcineurin and the immunophilins. We also show that at low concentrations FK506 and cyclosporin A enhance the phosphorylation of endogenous protein substrates in brain tissue and in intact PC12 cells, indicating that these drugs may inhibit phosphatase activity by interacting with the immunophilin-calcineurin complexes.

Factors responsible for the Ca2+‐dependent inactivation of calcineurin in brain

“…Almost complete inhibition (> 90%) is observed at 1/2M FK506. As expected from the high concentration FK506-binding protein (FKBP) reported in brain by Steiner et al [14] the inhibition does not require addition of exogenous FKBP. The high concentration of FK506 (1/,tM) needed for full inactivation compared to that required to inhibit calcineurin activity of Jurkat cell lysates (< 1 nM) [3] may reflect the presence of competing ligands, a 10-20-fold higher concentration of calcineurin in brain than in other tissues or both.…”

“…Endogenous inhibitory ligands could be responsible for the relatively low specific activity of calcineurin in crude brain extracts. The high concentration of the FK506-binding protein, FKBP, in brain [14] also suggests that it may be accompanied by equally high concentration of these putative regulatory ligands.…”

Molecular Neurobiology of Drug Addiction

“…Aspirin and all other nonsteroi dal antiinflammatory agents inhibit cyclo-oxygenase, the fIrst enzyme in the generation of prostaglandin, leu kotriene, and endoperoxide intracellular messengers (Piomelli and Greengard 1990). FK-506 and related im munosuppressive agents bind to a newly discovered class of protein, the immunophilins (also present at high levels in brain), that regulate the activity of specific pro tein phosphatases (see Steiner et al 1992). Lithium, one of the most effective psychotherapeutic agents avail able, directly regulates the activity of adenylyl cyclase, G proteins, and certain inositol phosphatases, actions that presumably result in the drug's antimanic and an tidepressant effects (see Hyman and Nestler 1993).…”

Higher intracerebral concentration of tacrolimus after intermittent than continuous administration to rats

“…Beyond this threshold concentration, the intracerebral concentration of tacrolimus will increase rapidly as the whole-blood concentration increases. Conversely, the level of FKBP in the brain is 10 times greater than that in other tissues, 24 and the extensive intracerebral binding of the drug to FKBP may result in high and sustained accumulation of tacrolimus in the brain.…”