More than apoptosis: Bcl-2 at ryanodine receptor channels Free

B-cell lymphoma-2 (Bcl-2), often upregulated in B-cell cancers, is an anti-apoptotic protein that scaffolds pro-apoptotic members of the Bcl-2 family at mitochondria in order to counteract their activity. In addition, Bcl-2 has a role in intracellular Ca2+ homeostasis and dynamics, which it exerts through targeting and modulating of Ca2+ transporters, including inositol 1,4,5-trisphosphate receptor (IP3R) and Ca2+ ATPases, at the ER and the plasma membrane. The N-terminal BH4 domain of Bcl-2 interacts with a region of the central modulatory domain of IP3R, which was found to resemble a highly conserved sequence of amino acids within ryanodine receptors (RyRs), the other main class of intracellular Ca2+-release channels. This resemblance prompted Geert Bultynck and colleagues to investigate whether Bcl-2 acts on RyRs, and the authors now provide evidence (p. 2782) for endogenous complexes between RyRs and Bcl-2 in rat hippocampi. By using purified proteins and peptides, the authors then demonstrate that Bcl-2, through its N-terminal BH4 domain, directly binds to the central domain of the RyR channels. The authors also address the molecular function of this interaction and show that Bcl-2 overexpression suppressed caffeine-triggered RyR-mediated Ca2+ signalling. Interestingly, the BH4 domain of Bcl-2 was sufficient to induce RyR inhibition, because delivering the BH4 domain of Bcl-2 as a peptide into HEK293 cell models or hippocampal neurons decreased RyR-mediated Ca2+ release. Thus, the results presented here clearly demonstrate that RyRs are targeted and inhibited by Bcl-2, therefore providing new insight into how Bcl-2 proteins control Ca2+ signalling and how they might be relevant in their emerging role regarding non-apoptotic processes.