Summary
The distribution of the mRNAs encoding the different isoforms of the catalytic subunit (A subunit) of calcineurin has been investigated in rat thymus and kidney using in situ hybridization histochemistry with specific antisense oligonucleotide probes. In the thymus, the mRNAs of the Aβ isoforms were the predominant transcripts and showed very intense hybridization signals in the cortical areas. The Aα mRNAs were expressed at low levels. Aβ2 mRNA was expressed at higher levels than Aβ3 mRNA, but no difference could be detected between the expression levels of Aα1 and Aα2. In the kidney, highest calcineurin A mRNA hybridization signals were found in the medulla. Signal intensities of Aα mRNAs were comparable to those of Aβ mRNAs. Aα1 mRNA level was extremely weak, and Aβ2 mRNA expression was slightly higher than Aβ3 mRNA expression. A tissue-specific distribution pattern of the alternatively spliced isoforms of calcineurin A, as suggested by these preliminary data from thymus and kidney, may be critical in understanding the toxic side-effects associated with the use of the immunosuppressive, calcineurin-inhibiting compounds cyclosporin A and FK506.
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Buttini, M., Limonta, S., Luyten, M. & Boddeke, I. (1993) Differential distribution of calcineurin Aα isoenzyme in mRNA's in rat brain. Naunyn Schmiedeberg's Arch. PharmacoL. 348, 679–83.
Buttini, M., Luyten, M., Limonta, S. & Boddeke, I. (1994) Distribution of calcineurin Aβ isoenzyme mRNA in rat brain: comparison with the Aα mRNA distribution. Neurosci. Res. ComM. 14, 9–16.
Dumont, F. J., Staruch, M. J., Koprak, S. L., Siekierka, J. J., Shirley-Lin, C., Harrison, R., Sewell, T., Kindt, V. M., Beattie, T. R., Wywratt, M. & Sigal, N. A. (1992) The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin. J. Exp. MeD. 176, 751–60.
Guerini, D. & Klee, C. B. (1989) Cloning of human calcineurin A: evidence for two isoenzymes and identification of a polyproline structural domain. Proc. Natl Acad. Sci. USA 86, 9183–87.
Hashimoto, Y., Perrino, B. A. & Soderling, T. R. (1990) Identification of an autoinhibitory domain in calcineurin. J. Biol. CheM. 265, 1924–27.
Ito, A., Hashimoto, T., Hirai, M., Takeda, T., Shuntoh, I., Kuno, T. & Tanaka, C. (1989) The complete primary structure of calcineurin A, a calmodulin binding protein homologous with protein phosphatases 1 and 2A. Biochem. Biophys. Res. CommuN. 163, 1492–97.
Kincaid, R. L., Giri, P. R., Higuchi, S., Tamura, J., Dixon, S. C., Marietta, C. A., Amorese, D. A. & Martin, B. M. (1990) Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using non-isotopic methods. J. Biol. CheM. 265, 11312–9.
Kincaid, R. L., Higuchi, S., Tamura, J., Giri, P. R. & Martensen, T. M. (1991) Structural isoforms of the catalytic subunit of calmodulin-dependent phosphoprotein phosphatase (calcineurin): deriving specifically by linking conserved and variable regions. Adv. Prot. Phosphatases 6, 73–8.
Kumano, K., Wang, G., Endo, T. & Kuwao, S. (1991) FK-506 induced nephrotoxicity in rats. Transplant. ProC. 23, 512–5.
Kuno, T., Takeda, T., Hirai, M., Ito, A. & Mukai, I. (1989) Evidence for a second isoform of the catalytic subunit of calmodulin-dependent phosphatase (calcineurin). Biochem. Biophys. Res. CommuN. 165, 1352–8.
Liu, J. (1993) FK506 and cyclosporin: molecular probes for studying intracellular signal transduction. Trends Pharmacol. ScI. 14, 182–9.
Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I. & Schreiber, S. L. (1991) Calcineurinis a common target of cyclophylin-cyclosporin A and FKBP-FK-506 complexes. Cell 66, 807–15.
Mason, J. (1989) Pharmacology of cyclosporine (sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals. Pharmacol. ReV. 41, 423–34.
Meister, B., Fryckstedt, J., Schalling, M., Cortes, R., Hokfelt, T., Aperia, A., Hemmings, H. C. Jr., Nairn, A. C., Ehrlich, M. & Greengard, P. (1989) Dopamine- and cAMP-regulated phosphoprotein (DARRP-32) and dopamine DA1 agonist-sensitive NA+, K+-ATPase in renal tubule cells. Proc. Natl Acad. Sci. USA 86, 8068–72.
Miyamoto, E. (1991) Rat mRNA for calcineurin A. Genbank accession number X57115.
Morris, S. M. Jr., Kepka-Lenhart, D., Mcgill, R. L., Curthoys, N. P. & Adler, S. (1992) Specific disruption of renal function and gene transcription by cyclosporin A. J. Biol. CheM. 267, 13768–71.
Moutabarrik, A., Ishibashi, M., Fukunaga, M., Kameoka, I., Kawaguchi, N., Takano, Y., Kokado, Y., Sonoda, T., Onishi, S., Takahra, S. & Okuyama, A. (1992) FK-506-induced kidney tubular cell injury. Transplantation 54, 1041–7.
Ouimet, C. C., Miller, P. E., Hemmings, H. C. Jr., Walaas, S. I. & Greengard, P. (1984) DARPP-32, a dopamine- and adenosine 3′,5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J. NeuroscI. 4, 111–24.
Polli, J. W., Billingsley, M. L. & Kincaid, R. L. (1991) Expression of the calmodulin-dependent protein phosphatase, calcineurin, in rat brain: developmental patterns and the role of nigrostriatal innervation. Dev. Brain. ReS. 63, 105–19.
Schwaninger, M., Blume, R., Oetjen, E. & Knepel, W. (1993) The immunosuppressive drugs cyclosporin A and FK506 inhibit calcineurin phosphatase activity and gene transcription mediated through the cAMP-responsive element in a nonimmune cell line. Naunyn Schmiedeberg's Arch. PharmacoL. 348, 541–5.
Takaishi, T., Saito, N., Kuno, T. & Tanaka, C. (1991) Differential distribution of the mNRA encoding two isoforms of the catalytic subunit of calcineurin in the rat brain. Biochem. Biophys. Res. ComM. 174, 393–8.
Verweij, C. L., Guidos, C. & Crabtree, G. R. (1990) Celltype specificity and activation requirements for NFAT-1 transcriptional activity determined by a new method using transgenic mice to assay transcriptional activity of an individual nuclear factor. J. Biol. CheM. 265, 15 788–95.
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Buttini, M., Limonta, S., Luyten, M. et al. Distribution of calcineurin A isoenzyme mRNAs in rat thymus and kidney. Histochem J 27, 291–299 (1995). https://doi.org/10.1007/BF00398971
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DOI: https://doi.org/10.1007/BF00398971