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FK506 binding proteins : cellular regulators of intracellular Ca2+ channels

MacMillan, Debbi (2013) FK506 binding proteins : cellular regulators of intracellular Ca2+ channels. European Journal of Pharmacology. ISSN 0014-2999 (In Press)

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Abstract

In many cell types the intracellular Ca2+ store performs a central role in the regulation of the cytosolic Ca2+ concentration ([Ca2+]c) , the elevation of which triggers diverse and fundamental activities from reproduction to apoptosis, as well as being the major triggr for contraction.Two distinct classses of Ca2+ release channels, which mobilize Ca2+ from the store, exist: the inositol 1,4,5-trisphosphate (IP3) receptor and the ryanodine receptor. Considerable attention has been directed towards the importance of modulatory proteins that interact with these channels including, FK506 binding proteins (FKBPs), FKBP12 and its isoform, FKBP12.6. Although FKBP12 was first identified as the principal intracellular target for the immunosuppressive drugs, FK506 and rapamycin, new insights into the role of FKBPs have since emerged. These regulatory proteins are reportedly important modulators of intracellular Ca2+ release. FKBPs may regulate ryanodine and IP3 receptors either directly, by binding to the cytoplasmic aspect of the channel, or indirectly via modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR). Dissociation of FKBP12 or FKBP12.6 from either Ca2+ release channel may increase, decrease or have no effect on ryanodine receptor- or IP3 receptor-mediated Ca2+ release. These important controversies may be attributed to FKBPs' ability to regulate the receptor indirectly via the kinase and phosphatase pathways modulated by the accessory proteins. This brief review discusses the regulation of intracellular ryanodine and IP3 receptor Ca2+ release channels by accessory FKBPs, with important implications for the role of FKBPs in the pathophysiology of a number of diseases.