image: Exemplary Ca2+ signaling microdomains. Cartoon illustration of various microdomains featured in different types of cells, all being artificially integrated in a hypothetical single cell. (1) Cardiac dyad. Single LTCC openings generate Ca2+ sparklets to activate a RYR2 Ca2+ nanospark in the cleft and a Ca2+ spark of 2 μm diameter in the surrounding space, as well as a Ca2+ blink in the connected ER/SR cistern. (2) Skeletal muscle triad (half structure illustrated). Arrayed RYR1 is mechanically gated by DHPR acting as the voltage sensor to initiate SR Ca2+ release, which, in turn, may activate nearby RYR3/β array via the CICR mechanism. (3) Subsurface cistern, to support subsurface sparks seen in smooth muscle cells and DRG neurons. (4) Clustered Orai1 and STIM1 forming an elemental unit for SOCE. Its digital operation gives rise to Ca2+ glows which morphology and kinetics are shaped by membranous structures like invadopodia. (5) Multimodal Ca2+ signaling microdomain. In human lung fibroblasts, Ca2+ flickers arise from both TRPM7 Ca2+ influx, sensing mechanical signals, and IP3R Ca2+ release, sensing chemotactic signal mediated by platelet-derived growth factor receptor (PDGFR) signaling pathway, and dynamically regulate the assembly and disassembly of cytoskeletal filaments, and thereby steer the direction of cell migration. (6) Mitochondria-associated membranes (MAMs), the contact sites between mitochondria and ER, are a central hub for Ca2+ signaling, apoptosis, autophagy and lipid biosynthesis. (7) ER surface Ca2+ microdomains, sites of phase separation of protein complex for specification of autophagosome initiation. (8) Perinuclear Ca2+ waves from the ER in the nuclear envelope, with high Ca2+ passing through the nuclear pores. (9) Golgi Ca2+ microdomain
Credit: Fujian Lu, Pengcheng Yang, Donghui Zhang, Xianhua Wang, Heping Cheng
The Advantages of the Digital System:
- Efficiency: Concentrated calcium within microdomains maximizes signaling efficiency.
- Specificity: Localized signaling ensures precise activation of target proteins.
- Complex Behavior: Coordinated activation of multiple microdomains enables complex cellular behaviors.
Future Research Directions:
- Understanding microdomain assembly: Investigate how calcium microdomains form and function.
- Exploring signalosome-microdomain interactions: Elucidate the interactions between calcium signalosome proteins and microdomains.
- Studying microdomain dysregulation in disease: Investigate the role of microdomain dysregulation in various diseases.
- Extending the digital principle to other signaling molecules: Explore the applicability of the digital principle to other signaling molecules.
This review offers a transformative view of calcium signaling, paving the way for further exploration of its intricate mechanisms and applications in understanding and treating diseases.
The work entitled “Thirty years of Ca2+ spark research: digital principle of cell signaling unveiled” was published on Biophysics Reports (published on Oct., 2024).
Journal
Biophysics Reports
Method of Research
Experimental study
Subject of Research
Cells
Article Title
Thirty years of Ca2+ spark research: digital principle of cell signaling unveiled
Article Publication Date
1-Oct-2024