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

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.