Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin

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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)525-534
Number of pages10
JournalMolecular Neurobiology
Issue number1
StatePublished - Jan 1 2019

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience


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