Bcl-2 and FKBP12 bind to IP3 and ryanodine receptors at overlapping sites: the complexity of protein–protein interactions for channel regulation

Abstract

The 12- and 12.6-kDa FK506-binding proteins, FKBP12 (12-kDa FK506-binding protein) and FKBP12.6 (12.6-kDa FK506-binding protein), have been implicated in the binding to and the regulation of ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs), both tetrameric intracellular Ca2+-release channels. Whereas the amino acid sequences responsible for FKBP12 binding to RyRs are conserved in IP3Rs, FKBP12 binding to IP3Rs has been questioned and could not be observed in various experimental models. Nevertheless, conservation of these residues in the different IP3R isoforms and during evolution suggested that they could harbour an important regulatory site critical for IP3R-channel function. Recently, it has become clear that in IP3Rs, this site was targeted by B-cell lymphoma 2 (Bcl-2) via its Bcl-2 homology (BH)4 domain, thereby dampening IP3R-mediated Ca2+ flux and preventing pro-apoptotic Ca2+ signalling. Furthermore, vice versa, the presence of the corresponding site in RyRs implied that Bcl-2 proteins could associate with and regulate RyR channels. Recently, the existence of endogenous RyR-Bcl-2 complexes has been identified in primary hippocampal neurons. Like for IP3Rs, binding of Bcl-2 to RyRs also involved its BH4 domain and suppressed RyR-mediated Ca2+ release. We therefore propose that the originally identified FKBP12-binding site in IP3Rs is a region critical for controlling IP3R-mediated Ca2+ flux by recruiting Bcl-2 rather than FKBP12. Although we hypothesize that anti-apoptotic Bcl-2 proteins, but not FKBP12, are the main physiological inhibitors of IP3Rs, we cannot exclude that Bcl-2 could help engaging FKBP12 (or other FKBP isoforms) to the IP3R, potentially via calcineurin.

FK506 Attenuated Pilocarpine-Induced Epilepsy by Reducing Inflammation in Rats

“…FK506, a calcineurin inhibitor, is a potent immunosuppressant for clinical prevention and treatment of allograft rejection (19–21). It exerts its immunosuppressive effect by binding to FK506 binding protein 12 (21, 22). Studies have shown that FK506 has neuroprotective and neurotrophic effects (23, 24).…”

Vitamin D, reactive oxygen species and calcium signalling in ageing and disease

“…What is remarkable about these two signalling systems is the way they interact with each other [4] (figure 1 [9] and RYRs [10,11], is reduced by ROS [12]. ROS can activate a number of TRP channels that gate Ca 2þ (e.g.…”

“…One of the main functions of Nrf2 is to maintain the cellular level of the redox buffer GSH [136], which is a critical factor in preventing AD [44]. The level of Bcl-2, which inhibits the ability of InsP 3 to activate the InsP 3 receptors [9] and the RYRs [10,11] (figure 1), is maintained by Nrf2 and Klotho, thereby reducing the level of Ca 2þ . The ability of Bcl-2 to reduce the symptoms of AD in transgenic mice [137,138] may be explained by this reduction in the activity of both the InsP 3 R and RYRs.…”

Dynamics expression of DmFKBP12/Calstabin during embryonic early development of Drosophila melanogaster

“…Molecular cloning of DmRyR cDNA provided the solid evidence of DmRyR expression in Drosophila lava [16]. As the crucial regulator of this CICR pathway along with binding protein of IP3R as well [47], in which four DmFKBP12 control opening of ER/SR DmRyR tetramer, the expression and function of DmFKBP12 should be carried out in the lava stage. Because of, as discussed above, RyR-mediated CICR exhibiting with calcium spark and calcium wave robusting from fertilization of many animals [48–51], it is judicious that the DmRyR-FKBP12 complex functions as early as the same stage.…”