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Purinergic P2X7 receptors (P2X7Rs) are trimeric nonselective cation channels possessing three intrasubunit orthosteric binding sites and unidentified number of allosteric binding sites. In previous work, we showed that the same receptor is capable of exhibiting sensitization and pore dilation (leading to the formation of biphasic currents and cell death) and/or desensitization (leading to a decline in current amplitude and cell life signaling) during sustained application of orthosteric agonists, depending on their concentrations. This was done in part by developing a 12-state Markov model consisting of naive (not previously exposed to orthosteric agonist), desensitized, and sensitized/dilated states that reproduced whole-cell current recordings generated experimentally. In this model, we assumed that the occupancy of one or two ATP-binding sites of naive receptors favored transition from open to desensitized states, whereas the occupancy of the third binding site favored receptor sensitization. Our goal here is to extend this modeling study by examining how these model cells behave under various ionic conditions in the medium, including those that contain large organic cation N-methylD-glucamine (NMDG + ) or divalent cation such as Ca 2+ . We illustrate how the two main gating patterns behave under these ionic conditions and determine why the shift in reversal potential and the dilation of the channels are accompanied paradoxically by a decrease in the total conductance during voltage ramp protocols. The model adds more evidence to our previous hypothesis, suggesting that dilation is masking desensitization. Our results also indicate that the allosteric sites through which divalent cations inhibit P2X7R should be extracellularly located.

Deciphering the Kinetic and Gating Properties of Purinergic P2X7 Receptor Channels