Mechanisms and regulation of Ca2+ leakage from the ER (A04)

• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2011 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 157660137

We identified Sec61 complexes as major Ca2+ leak channels of the mammalian endoplasmic reticulum (ER). While the Ca2+ leak is regulated by allosteric effectors such as BiP or TRAP, a point mutation in the Sec61 complex can cause a dysregulated Ca2+ flux, which we characterized as the root of primary antibody deficiency in humans. Recently, we decoded the signaling function of the Sec61-mediated Ca2+ leak. In our view, it serves as the signal of an ATP- Ca2+ cycle that replenishes the ATP demand of the ER via SLC35B1. Next, we will study novel disease-associated Sec61 mutants, identify pharmacological modulators of the Sec61-mediated Ca2+ flux, characterize its regulation in sub-domains of the ER and determine its contribution to ER energy homeostasis.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 894: Ca2+-Signalling: Molecular Mechanisms and Integrative Functions
• Applicant Institution: Universität des Saarlandes
• Project Heads: Professor Dr. Adolfo Cavalié; Dr. Sven Lang, since 1/2019; Professor Dr. Richard Zimmermann, until 12/2018