Novel insights in the interplay between ryanodine receptors and Bcl-2 proteins.

Intracellular Ca2+ signalling controls a wide array of cellular processes ranging from cell proliferation, cell survival, autophagy to cell death. Cells express an extensive amount of proteins involved in regulating these intracellular Ca2+ signals. The ryanodine receptor (RyR)-protein family is a family of sarco/endoplasmic reticulum-located Ca2+-release channels expressed in several excitable cells including neurons, muscle cells and the hearth. The B-cell lymphoma (Bcl) 2-protein family is well known for its functions in apoptosis regulation. Anti-apoptotic Bcl-2-family members are also known to modulate intracellular Ca2+ signalling as an important aspect of their anti-apoptotic function. Recently we identified RyRs (RyR1, RyR2, RyR3), as novel targets of anti-apoptotic Bcl-2-family members. In the framework of this project, we plan to address two topics. In order to identify a potential (patho-)physiological role for the Bcl-2 RyR interaction, i) we will assess the impact of disease-linked mutations in RyR2 on Bcl-2-mediated regulation of these RyRs and ii) asses the impact of RyR activity on autophagy.