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Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin

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Abstract

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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Acknowledgements

Research reported in this publication was supported in part by grants from the National Eye Institute (EY014227 and EY022774), the Institute on Aging (AG022550 and AG027956), the National Center for Research Resources, and National Institute of General Medical Sciences (RR027093) of the National Institutes of Health (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research and a Challenge Grant from Research to Prevent Blindness (PK) is gratefully acknowledged.

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  1. Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA

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

  2. Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA

    Peter Koulen

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  1. Michael A. Grillo
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  2. Stephanie L. Grillo
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Correspondence to Peter Koulen.

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Grillo, M.A., Grillo, S.L., Gerdes, B.C. et al. Control of Neuronal Ryanodine Receptor-Mediated Calcium Signaling by Calsenilin. Mol Neurobiol 56, 525–534 (2019). https://doi.org/10.1007/s12035-018-1080-2

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