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The Journal of Neuroscience, September 1, 1999, 19(17):7289-7299
Allosteric Control of Gating and Kinetics at P2X4
Receptor Channels
Baljit S.
Khakh1,
William R.
Proctor2,
Thomas
V.
Dunwiddie2,
Cesar
Labarca1, and
Henry A.
Lester1
1 Division of Biology, California Institute of
Technology, Pasadena, California 91125, and 2 University of
Colorado Health Sciences Center and Department of Veterans Affairs
Medical Center, Denver, Colorado 80262
The CNS abundantly expresses P2X receptor channels for ATP;
of these the most widespread in the brain is the P2X4
channel. We show that ivermectin (IVM) is a specific positive
allosteric effector of heterologously expressed P2X4 and
possibly of heteromeric P2X4/P2X6
channels, 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  , -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.
Key words:
ATP; ivermectin; ion channel; allosteric; modulation; P2X; purinoceptor
Copyright © 1999 Society for Neuroscience 0270-6474/99/19177289-11$05.00/0
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