Regulation of ADAM10 activity through microdomain-dependent intracellular calcium changes
Federico Guillermo Gharzia1, Ahmad Aljohmani1, Andreas Beck2
1Molecular Pharmacology, PZMS, Saarland University, Campus Homburg Building 46, 66421, Homburg, Germany.
Abstract:
A disintegrin and metalloproteinases (ADAMs) are transmembrane proteases that cleave other proteins close to the surface in a process called shedding. The prominent member ADAM10 has been linked to several pathologies such as Alzheimer's disease, bacterial infection, cancer development and metastasis. Although the regulation of the ADAM10 activity by calcium influx and calmodulin inhibition has been reported, the spatiotemporal regulation of Ca2+-dependent ADAM10 activation and the required source of Ca2+ ions have not been thoroughly studied. In the present study, we observed the rapid Ca2+-dependent activation of ADAM10 in A549 lung carcinoma cells upon stimulation with ionomycin. The calmodulin-inhibitors trifluoperazine and ophiobolin A mediated delayed activation of ADAM10, which apparently did not depend on intracellular Ca2+ in the case of trifluoperazine. Furthermore, the surface translocation and release of ADAM10 in extracellular vesicles exhibited different kinetics and were only partially linked to catalytic activation. Finally, ADAM10 activation was observed after the entry of Ca2+ through certain channels, such as canonical members of transient receptor potential (TRP) channels. Therefore, the opening of particular channels for Ca2+ entry points and subsequent Ca2+ flux as well as the temporal aspects of the consequent increase in Ca2+ levels, must be considered for future therapeutic options involving the increasing or decreasing ADAM10 activity.
Insights
The study reveals that calcium influx rapidly activates ADAM10 protease, influencing its shedding and release. Understanding calcium channel roles is crucial for therapeutic strategies targeting ADAM10 activity.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Medicine
Background:
- A disintegrin and metalloproteinases (ADAMs) are transmembrane proteases involved in protein shedding.
- ADAM10, a key member, is implicated in diseases like Alzheimer's, cancer, and infections.
- Regulation of ADAM10 by calcium and calmodulin is known, but spatiotemporal control and calcium sources remain unclear.
Purpose of the Study:
- To investigate the spatiotemporal regulation of calcium-dependent ADAM10 activation.
- To identify the specific sources of calcium ions required for ADAM10 activation.
- To explore the relationship between ADAM10 activation, surface translocation, and release.
Main Methods:
- Stimulation of A549 lung carcinoma cells with ionomycin to induce calcium influx.
- Treatment with calmodulin inhibitors (trifluoperazine, ophiobolin A) to assess their effect on ADAM10 activation.
- Analysis of ADAM10 surface translocation and release in extracellular vesicles.
- Investigation of calcium entry through transient receptor potential (TRP) channels.
Main Results:
- Rapid, calcium-dependent activation of ADAM10 was observed upon ionomycin stimulation.
- Calmodulin inhibitors induced delayed ADAM10 activation, with trifluoperazine showing apparent independence from intracellular calcium.
- Surface translocation and extracellular vesicle release of ADAM10 occurred with different kinetics and were only partially linked to catalytic activation.
- ADAM10 activation was triggered by calcium entry via specific channels, including TRP channels.
Conclusions:
- The rapid activation of ADAM10 is critically dependent on calcium influx.
- The kinetics of ADAM10 translocation and shedding differ from its catalytic activation.
- Specific calcium channels and the temporal dynamics of intracellular calcium levels are key factors in ADAM10 regulation.
- Consideration of calcium channel activity and calcium flux dynamics is essential for developing therapies targeting ADAM10.
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