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Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases,
Lin-Hua Jiang1, Jocelyn M Baldwin, Sebastien Roger
1School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds Leeds, UK.
Abstract:
The mammalian P2X7 receptors (P2X7Rs), a member of the ionotropic P2X receptor family with distinctive functional properties, play an important part in mediating extracellular ATP signaling in health and disease. A clear delineation of the molecular mechanisms underlying the key receptor properties, such as ATP-binding, ion permeation, and large pore formation of the mammalian P2X7Rs, is still lacking, but such knowledge is crucial for a better understanding of their physiological functions and contributions in diseases and for development of therapeutics. The recent breakthroughs in determining the atomic structures of the zebrafish P2X4.1R in the closed and ATP-bound open states have provided the long-awaited structural information. The human P2RX7 gene is abundant with non-synonymous single nucleotide polymorphisms (NS-SNPs), which generate a repertoire of human P2X7Rs with point mutations. Characterizations of the NS-SNPs identified in patients of various disease conditions and the resulting mutations have informed previously unknown molecular mechanisms determining the mammalian P2X7R functions and diseases. In this review, we will discuss the new insights into such mechanisms provided by structural modeling and recent functional and genetic linkage studies of NS-SNPs.
Insights
Mammalian P2X7 receptors (P2X7Rs) mediate ATP signaling. Recent structural and genetic studies reveal molecular mechanisms of P2X7R function and disease, aiding therapeutic development.
Area of Science:
- Molecular biology
- Neuroscience
- Pharmacology
Background:
- Mammalian P2X7 receptors (P2X7Rs) are critical for extracellular ATP signaling in health and disease.
- Understanding P2X7R mechanisms (ATP-binding, ion permeation, pore formation) is vital for physiology and therapeutics.
- Recent structural data from zebrafish P2X4.1R offers insights into receptor states.
Purpose of the Study:
- To review recent advances in understanding P2X7R molecular mechanisms.
- To highlight the role of non-synonymous single nucleotide polymorphisms (NS-SNPs) in P2X7R function and disease.
- To integrate structural, functional, and genetic data for a comprehensive view of P2X7R.
Main Methods:
- Structural modeling based on zebrafish P2X4.1R atomic structures.
- Functional characterization of human P2X7Rs with NS-SNPs.
- Genetic linkage studies in patient populations.
Main Results:
- Atomic structures illuminate P2X7R gating and pore formation.
- NS-SNPs in the human P2RX7 gene lead to diverse P2X7R variants.
- Patient-derived NS-SNPs reveal disease-associated functional alterations.
Conclusions:
- Structural and genetic insights are advancing the understanding of P2X7R molecular mechanisms.
- P2X7R variants due to NS-SNPs contribute to various disease pathologies.
- This knowledge is crucial for developing targeted P2X7R therapeutics.
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