Allosteric control of gating and kinetics at P2X(4) receptor channels

The CNS abundantly expresses P2X receptor channels for ATP; of these the mo st widespread in the brain is the P2X(4) channel. We show that ivermectin ( IVM) is a specific positive allosteric effector of heterologously expressed P2X(4) and possibly of heteromeric P2X(4)/P2X(6) channels, but not of P2X( 2), P2X(3), P2X(2)/ P2X(3), or P2X(7) channels. In the submicromolar range (EC50, similar to 250 nM) the action of IVM was rapid and reversible, resul ting in increased amplitude and slowed deactivation of P2X(4) channel curre nts evoked by ATP. IVM also markedly increased the potency of ATP and that of the normally low-potency agonist alpha,beta-methylene-ATP in a use- and voltage-independent manner without changing the ion selectivity of P2X(4) c hannels. Therefore, IVM evokes a potent pharmacological gain-of-function ph enotype that is specific for P2X(4) channels. We also tested whether IVM co uld modulate endogenously expressed P2X channels in the adult trigeminal me sencephalic nucleus and hippocampal CA1 neurons. Surprisingly, IVM produced no significant effect on the fast ATP-evoked inward currents in either typ e of neuron, despite the fact that IVM modulated P2X(4) channels heterologo usly expressed in embryonic hippocampal neurons. These results suggest that homomeric P2X(4) channels are not the primary subtype of P2X receptor in t he adult trigeminal mesencephalic nucleus and in hippocampal CA1 neurons.