Allosteric Modulation
The sensitivity of P2X receptors to ATP is strongly modulated by changes in extracellular pH and by the presence of heavy metals (e.g. zinc and cadmium). For example, the ATP sensitivity of P2X1, P2X3 and P2X4 receptors is attenuated when the extracellular pH<7, whereas the ATP sensitivity of P2X2 is significantly increased. On the other hand, zinc potentiates ATP-gated currents through P2X2, P2X3 and P2X4, and inhibits currents through P2X1. The allosteric modulation of P2X receptors by pH and metals appears to be conferred by the presence of histidine side chains in the extracellular domain. In contrast to the other members of the P2X receptor family, P2X4 receptors are also very sensitive to modulation by the macrocyclic lactone, ivermectin. Ivermectin potentiates ATP-gated currents through P2X4 receptors by increasing the open probability of the channel in the presence of ATP, which it appears to do by interacting with the transmembrane domains from within the lipid bilayer.
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