Purinergic Receptors We have previously described (see 2010 and 2012 reports) a kinetic model, developed in collaboration with the Stojilkovic experimental lab (NICHD), of the P2X7 receptor. This receptor is a ligand-gated ion channel activated by extracellular ATP and is expressed ubiquitously, including in pituitary cells and macrophages. At low concentrations of ATP, this ligand-gated calcium channel acts much like other members of the P2X family, but prolonged or repeated exposure to high ATP concentrations causes it to dilate and gate a massive influx of calcium. This unusual and complex behavior had led to proposals that the normal and super-normal currents are due to two different channels, but the model, a Markov state model with 8 states, showed that a single channel could play both roles. P2X7 can act both as a conventional calcium channel and as switch between a mode of cell growth and differentiation, when calcium is small, and a mode of programmed cell death, when calcium influx is large. This could be an important part of how the immune system maintains a balance between responding appropriately and over-reacting to inflammation. A polymorphism in the P2X7 receptor has been proposed as a susceptibility gene for the NOD mouse, a model for type 1 diabetes. We have previously modeled P2X2 receptors as well as P2X7 (See Ref. # 1, 2012 report). The current through this receptor rapidly shuts off in the face of maintained ATP but the model and experiments showed that the receptor nonetheless dilates, because it gains the ability to conduct large organic cations after stimulation with ATP. The model showed that the dilation was masked by desensitization. In the current report period, we returned to the P2X7 receptor and added desensitization, a feature that was known to be present but was neglected in the first iteration in order to keep the focus on the key features of dilation and memory. The models of the two receptors are structurally very similar but differ quantitatively in the transition rates. The updated P2X7 model now exhibits both dilation and desensitization, but, in contrast to P2X2, dilation dominates. The similarity between the two models lends support to our overall hypothesis that P2X receptors have a common core of features but differ quantitatively to achieve different end behaviors. We plan to test this hypothesis further by extending the model to other members of the P2X family.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$62,343
Indirect Cost
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State
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Zemkova, Hana; Khadra, Anmar; Rokic, Milos B et al. (2015) Allosteric regulation of the P2X4 receptor channel pore dilation. Pflugers Arch 467:713-26
Khadra, Anmar; Tomic, Melanija; Yan, Zonghe et al. (2013) Dual gating mechanism and function of P2X7 receptor channels. Biophys J 104:2612-21