Extracellular histone proteins activate P2XR7 channel current.
Rua'a Al-Aqtash1, Maxwell S Ross1, Daniel M Collier1
1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA.
The Journal of General Physiology
|May 18, 2023
Summary
Extracellular histones activate the P2XR7 channel, a non-selective cation channel, in endothelial cells. This finding reveals a novel mechanism for P2XR7 activation by histone proteins.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Extracellular histones are elevated after injury and innate immune response activation.
- Histones increase endothelial cell (EC) Ca2+ influx and PI labeling, paradoxically decreasing vasodilation.
- This suggests activation of an EC-resident non-selective cation channel.
Purpose of the Study:
- To test if the ionotropic purinergic receptor 7 (P2XR7), a non-selective cation channel, is activated by histone proteins.
- To investigate the mechanism of P2XR7 activation by histones.
Main Methods:
- Expressed mouse P2XR7 in heterologous cells.
- Measured inward cation current using two-electrode voltage clamp (TEVC).
- Utilized ATP and histone proteins as agonists and various P2XR7 antagonists.
Main Results:
- Cells expressing P2XR7 showed robust ATP- and histone-evoked inward cation currents.
- Histone-evoked currents exhibited slower decay kinetics compared to ATP-evoked currents.
- Selective P2XR7 antagonists did not inhibit histone-evoked currents, suggesting a distinct allosteric activation mechanism.
Conclusions:
- P2XR7 is necessary and sufficient for histone-evoked inward cation currents in a heterologous expression system.
- Histone proteins activate P2XR7 through a novel allosteric mechanism.
- This finding provides insight into the role of extracellular histones in vascular responses.
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