TY - JOUR T1 - Allosteric Control of Gating and Kinetics at P2X<sub>4</sub>Receptor Channels JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7289 LP - 7299 DO - 10.1523/JNEUROSCI.19-17-07289.1999 VL - 19 IS - 17 AU - Baljit S. Khakh AU - William R. Proctor AU - Thomas V. Dunwiddie AU - Cesar Labarca AU - Henry A. Lester Y1 - 1999/09/01 UR - http://www.jneurosci.org/content/19/17/7289.abstract N2 - The CNS abundantly expresses P2X receptor channels for ATP; of these the most widespread in the brain is the P2X4channel. We show that ivermectin (IVM) is a specific positive allosteric effector of heterologously expressed P2X4 and possibly of heteromeric P2X4/P2X6channels, but not of P2X2, P2X3, P2X2/P2X3, or P2X7 channels. In the submicromolar range (EC50, ∼250 nm) the action of IVM was rapid and reversible, resulting in increased amplitude and slowed deactivation of P2X4 channel currents evoked by ATP. IVM also markedly increased the potency of ATP and that of the normally low-potency agonist α,β-methylene-ATP in a use- and voltage-independent manner without changing the ion selectivity of P2X4 channels. Therefore, IVM evokes a potent pharmacological gain-of-function phenotype that is specific for P2X4 channels. We also tested whether IVM could modulate endogenously expressed P2X channels in the adult trigeminal mesencephalic nucleus and hippocampal CA1 neurons. Surprisingly, IVM produced no significant effect on the fast ATP-evoked inward currents in either type of neuron, despite the fact that IVM modulated P2X4 channels heterologously expressed in embryonic hippocampal neurons. These results suggest that homomeric P2X4 channels are not the primary subtype of P2X receptor in the adult trigeminal mesencephalic nucleus and in hippocampal CA1 neurons. ER -