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Proteomics to Identify Proteins Interacting with P2X2 Ligand-Gated Cation Channels
Published on: May 18, 2009
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Synthetic testosterone derivatives modulate rat P2X2 and P2X4 receptor channel gating
Sonja Sivcev1,2, Barbora Slavikova3, Marian Rupert1,4
1Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
Journal of Neurochemistry
|May 10, 2019
Summary
Testosterone derivatives, unlike other sex steroids, modulate P2X receptors (P2XRs). These compounds enhance P2X2R and P2X4R activity, suggesting a role for steroid-P2XR interactions in cellular signaling.
Area of Science:
- Neuropharmacology and Molecular Biology
- Ion Channel Modulation
- Steroid Hormone Signaling
Background:
- P2X receptors (P2XRs) are ATP-gated ion channels known to be modulated by various compounds, including steroids.
- While some steroids modulate P2XRs, sex hormones like estradiol and progesterone are generally considered inactive.
- The specific role of testosterone and its derivatives in modulating P2XRs remains largely unexplored.
Purpose of the Study:
- To investigate the hypothesis that testosterone and its derivatives modulate the activity of P2X receptors.
- To examine the effects of testosterone derivatives on specific P2XR subtypes (P2X2R, P2X4R, P2X7R) and native channels.
- To elucidate the structural determinants of testosterone derivative interactions with P2XRs.
Main Methods:
- Electrophysiological recordings (whole-cell patch-clamp) of recombinant and native P2XRs.
- Application of native testosterone and a series of its 17β-ester derivatives.
- Analysis of structure-activity relationships based on lipophilicity and alkyl chain length.
Main Results:
- Testosterone derivatives, particularly 17β-ester derivatives, rapidly and positively modulate P2X2R and P2X4R activity.
- These derivatives are generally more potent modulators than endogenous testosterone, with effects dependent on lipophilicity and C-17 alkyl chain length.
- Testosterone derivatives potentiate native channels, enhance ATP sensitivity, alter desensitization kinetics of P2X4R, and antagonize ivermectin's effects.
Conclusions:
- Testosterone derivatives are potent allosteric modulators of specific P2XR subtypes (P2X2R, P2X4R).
- The interaction of testosterone derivatives with P2XRs is influenced by their chemical structure, specifically lipophilicity and alkyl chain length.
- These findings suggest a potential role for steroid-P2XR interactions in cellular physiology and highlight the ivermectin binding site as a potential target for steroid-induced modulation.
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