P2X4 Receptor in Silico and Electrophysiological Approaches Reveal Insights of Ivermectin and Zinc Allosteric Modulation

@article{Latapiat2017P2X4RI,
  title={P2X4 Receptor in Silico and Electrophysiological Approaches Reveal Insights of Ivermectin and Zinc Allosteric Modulation},
  author={Ver{\'o}nica Latapiat and Felipe E. Rodr{\'i}guez and Francisca Godoy and Felipe A. Montenegro and Nelson P Barrera and Juan Pablo Huidobro-Toro},
  journal={Frontiers in Pharmacology},
  year={2017},
  volume={8}
}
Protein allosteric modulation is a pillar of metabolic regulatory mechanisms; this concept has been extended to include ion channel regulation. P2XRs are ligand-gated channels activated by extracellular ATP, sensitive to trace metals and other chemicals. By combining in silico calculations with electrophysiological recordings, we investigated the molecular basis of P2X4R modulation by Zn(II) and ivermectin, an antiparasite drug currently used in veterinary medicine. To this aim, docking studies… 

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References

SHOWING 1-10 OF 69 REFERENCES

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

TLDR
The previous and current findings suggest that the ethanol and IVM action pocket in P2X4Rs formed by positions 42, 46, 331, and 336 presents a potential target for medication development for alcohol use disorders.

Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation.

Identification of P2X4 receptor transmembrane residues contributing to channel gating and interaction with ivermectin

TLDR
Cysteine-scanning mutagenesis of rat P2X4-TMs was used to identify and map residues of potential importance for channel gating and interaction with IVM, finding 12 residues that were consistent with helical topology of both TMs.

Roles of the lateral fenestration residues of the P2X4 receptor that contribute to the channel function and the deactivation effect of ivermectin

TLDR
Data indicate that conserved amino acids within the regions linking the ectodomain with the pore-forming transmembrane domain meaningfully contribute to signal transduction and channel gating in P2X receptors.

Activation and Regulation of Purinergic P2X Receptor Channels

TLDR
Data obtained from numerous site-directed mutagenesis experiments accumulated during the last 15 years are discussed with reference to the crystal structure, allowing a structural interpretation of the molecular basis of orthosteric and allosteric ligand actions.

Structural basis for subtype-specific inhibition of the P2X7 receptor

TLDR
Crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists are presented and it is proposed that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP- binding pocket.

Allosteric modulation of ligand gated ion channels by ivermectin.

TLDR
What is currently known about ivermectin binding and modulation of Cys-loop receptor family of ligand-gated ion channels and what are the critical structural determinants underlying potentiation of the P2X4 receptor channel are reviewed.

Dependence of Purinergic P2X Receptor Activity on Ectodomain Structure*

TLDR
Results indicate the relevance of interaction between the ectodomain and flanking regions around the transmembrane domains on ligand potency and receptor activation and positively correlates with the rate of receptor desensitized but does not affect the C-terminal-specific pattern of desensitization.

Deciphering the regulation of P2X4 receptor channel gating by ivermectin using Markov models

TLDR
A two-layer model of P2X4R kinetics suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites.

Dissecting the Facilitator and Inhibitor Allosteric Metal Sites of the P2X4 Receptor Channel

TLDR
It is concluded that this region of the P2X4 receptor has a pocket for trace metal coordination with two distinct and separate facilitator and inhibitor metal allosteric sites highlighting the role of trace metals in neuronal excitability.
...