Journal Article

Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin

Gerdes, Bryan C., Grillo, Michael A., Grillo, Stephanie L., Koulen, Peter, Kraus, Jacob G.

2019

Overview

Calsenilin is a calcium ion (Ca 2+ )-binding protein involved in regulating the intracellular concentration of Ca 2+ , a second messenger that controls multiple cellular signaling pathways. The ryanodine receptor (RyR) amplifies Ca 2+ signals entering the cytoplasm by releasing Ca 2+ from endoplasmic reticulum (ER) stores, a process termed calcium-induced calcium release (CICR). Here, we describe a novel mechanism, in which calsenilin controls the activity of neuronal RyRs. We show calsenilin co-localized with RyR2 and 3 in the ER of mouse hippocampal and cortical neurons using immunocytochemistry. The underlying protein-protein interaction between calsenilin and the RyR was determined in mouse central nervous system (CNS) neurons using immunoprecipitation studies. The functional relevance of this interaction was assayed with single-channel electrophysiology. At low physiological Ca 2+ concentrations, calsenilin binding to the cytoplasmic face of neuronal RyRs decreased the RyR’s open probability, while calsenilin increased the open probability at high physiological Ca 2+ concentrations. This novel molecular mechanism was studied further at the cellular level, where faster release kinetics of caffeine-induced Ca 2+ release were measured in SH-SY5Y neuroblastoma cells overexpressing calsenilin. The interaction between calsenilin and neuronal RyRs reveals a new regulatory mechanism and possibly a novel pharmacological target for the control of Ca 2+ release from intracellular stores.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Caffeine / Caffeine - pharmacology / Calcium (intracellular) / Calcium (reticular) / Calcium - metabolism / Calcium Signaling - drug effects / Calcium signalling / Calcium-binding protein / Cell Biology / Cell Line, Tumor / Central nervous system / Cytoplasm / Electrophysiology / Endoplasmic reticulum / Hippocampus / Humans / Immunocytochemistry / Immunoprecipitation / Intracellular / Intracellular signalling / Kinetics / Kv Channel-Interacting Proteins - metabolism / Mice, Inbred C57BL / Neurobiology / Neuroblasts / Neurology / Neurons - drug effects / Neurons - metabolism / Neurosciences / Physiology / Protein Binding - drug effects / Protein interaction / Proteins / Rats, Sprague-Dawley / Ryanodine Receptor Calcium Release Channel - metabolism / Ryanodine receptors