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

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.

• Authors: Michael A Grillo, Stephanie L Grillo, Bryan C Gerdes, Jacob G Kraus, Peter Koulen
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 56 Issue 1 Pg. 525-534 (Jan 2019) ISSN: 1559-1182 [Electronic] United States
• PMID: 29730765 (Publication Type: Journal Article)

Chemical References

• Kv Channel-Interacting Proteins
• Ryanodine Receptor Calcium Release Channel
• Caffeine
• Calcium

Topics

• Animals
• Caffeine (pharmacology)
• Calcium (metabolism)
• Calcium Signaling (drug effects)
• Cell Line, Tumor
• Humans
• Kinetics
• Kv Channel-Interacting Proteins (metabolism)
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism)
• Protein Binding (drug effects)
• Rats, Sprague-Dawley
• Ryanodine Receptor Calcium Release Channel (metabolism)