Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic
Cristina I López-Sanjurjo1, Stephen C Tovey, David L Prole
1Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Journal of Cell Science
|October 26, 2012
Summary
Lysosomes actively take up calcium (Ca2+), influencing cellular signaling. Inhibiting this uptake amplifies Ca2+ signals originating from the endoplasmic reticulum (ER).
Area of Science:
- Cell Biology
- Calcium Signaling
- Endomembrane System Dynamics
Background:
- Intracellular calcium (Ca2+) signals are crucial for cellular functions, primarily regulated by plasma membrane and endoplasmic reticulum (ER) channels.
- Lysosomes possess Ca2+ channels involved in endo-lysosomal trafficking and signaling, but their role in Ca2+ signal regulation remains largely uninvestigated.
Purpose of the Study:
- To explore the unexplored role of lysosomal Ca2+ uptake in modulating cellular Ca2+ signaling.
- To investigate how inhibiting lysosomal Ca2+ uptake affects Ca2+ signals initiated by inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation.
Main Methods:
- Inhibition of lysosomal Ca2+ uptake using bafilomycin A1 (dissipating H+ gradient), glycyl-L-phenylalanine 2-naphthylamide (membrane perforation), and vacuolin (inhibiting fusion).
- Measurement of Ca2+ signals evoked by receptor stimulation, Ins(1,4,5)P3 photolysis, and ER Ca2+ pump inhibition.
- Video-imaging with total internal reflection fluorescence microscopy to observe lysosome-ER interactions.
Main Results:
- Inhibition of lysosomal Ca2+ uptake significantly increased Ca2+ signals evoked by Ins(1,4,5)P3-mediated pathways.
- Bafilomycin A1 amplified Ca2+ signals and slowed their recovery, indicating a role for lysosomal uptake in signal termination.
- Store-operated Ca2+ entry-mediated Ca2+ signals remained unaffected by lysosomal Ca2+ uptake inhibition.
- Lysosomes were observed to be motile and closely associated with the ER, facilitating selective Ca2+ accumulation.
Conclusions:
- Lysosomes play a significant, previously unrecognized role in regulating intracellular Ca2+ signaling by actively taking up Ca2+.
- The close proximity of lysosomes to the ER enables efficient sequestration of Ca2+ released by Ins(1,4,5)P3 receptors, shaping Ca2+ signal dynamics.
- Targeting lysosomal Ca2+ uptake represents a potential strategy for modulating Ca2+ signaling pathways.
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