Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin.

Calsenilin is a calcium ion (Ca²⁺)-binding protein involved in regulating the intracellular concentration of Ca²⁺, a second messenger that controls multiple cellular signaling pathways. The ryanodine receptor (RyR) amplifies Ca²⁺ signals entering the cytoplasm by releasing Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ concentrations. This novel molecular mechanism was studied further at the cellular level, where faster release kinetics of caffeine-induced Ca²⁺ 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 Ca²⁺ release from intracellular stores.

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