Lithocholic acid inhibits P2X2 and potentiates P2X4 receptor channel gating
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
32652201
DOI
10.1016/j.jsbmb.2020.105725
PII: S0960-0760(20)30250-8
Knihovny.cz E-resources
- Keywords
- ATP, Allosteric modulation, Bile acids, Ivermectin, Lithocholic acid, Purinergic P2X receptors,
- MeSH
- Pituitary Gland, Anterior cytology drug effects physiology MeSH
- Purinergic P2X Receptor Agonists pharmacology MeSH
- Purinergic P2X Receptor Antagonists pharmacology MeSH
- Ion Channel Gating drug effects MeSH
- HEK293 Cells MeSH
- Hypothalamus cytology drug effects physiology MeSH
- Lithocholic Acid analogs & derivatives pharmacology MeSH
- Humans MeSH
- Neurons drug effects physiology MeSH
- Rats, Wistar MeSH
- Receptors, Purinergic P2X2 physiology MeSH
- Receptors, Purinergic P2X4 physiology MeSH
- Receptors, Purinergic P2X7 physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Purinergic P2X Receptor Agonists MeSH
- Purinergic P2X Receptor Antagonists MeSH
- Lithocholic Acid MeSH
- Receptors, Purinergic P2X2 MeSH
- Receptors, Purinergic P2X4 MeSH
- Receptors, Purinergic P2X7 MeSH
The family of ATP-gated purinergic P2X receptors comprises seven bunits (P2X1-7) that are unevenly distributed in the central and peripheral nervous systems as well as other organs. Endogenous modulators of P2X receptors are phospholipids, steroids and neurosteroids. Here, we analyzed whether bile acids, which are natural products derived from cholesterol, affect P2X receptor activity. We examined the effects of primary and secondary bile acids and newly synthesized derivatives of lithocholic acid on agonist-induced responses in HEK293T cells expressing rat P2X2, P2X4 and P2X7 receptors. Electrophysiology revealed that low micromolar concentrations of lithocholic acid and its structural analog 4-dafachronic acid strongly inhibit ATP-stimulated P2X2 but potentiate P2X4 responses, whereas primary bile acids and other secondary bile acids exhibit no or reduced effects only at higher concentrations. Agonist-stimulated P2X7 responses are significantly potentiated by lithocholic acid at moderate concentrations. Structural modifications of lithocholic acid at positions C-3, C-5 or C-17 abolish both inhibitory and potentiation effects to varying degrees, and the 3α-hydroxy group contributes to the ability of the molecule to switch between potentiation and inhibition. Lithocholic acid allosterically modulates P2X2 and P2X4 receptor sensitivity to ATP, reduces the rate of P2X4 receptor desensitization and antagonizes the effect of ivermectin on P2X4 receptor deactivation. Alanine-scanning mutagenesis of the upper halve of P2X4 transmembrane domain-1 revealed that residues Phe48, Val43 and Tyr42 are important for potentiating effect of lithocholic acid, indicating that modulatory sites for lithocholic acid and ivermectin partly overlap. Lithocholic acid also inhibits ATP-evoked currents in pituitary gonadotrophs expressing native P2X2, and potentiates ATP currents in nonidentified pituitary cells expressing P2X4 receptors. These results indicate that lithocholic acid is a bioactive steroid that may help to further unveil the importance of the P2X2, and P2X4 receptors in many physiological processes.
Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic
Institute of Physiology Czech Academy of Sciences Prague Czech Republic
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