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Allosteric Control of Gating and Kinetics at P2X₄ Receptor Channels

Khakh, Baljit S. and Proctor, William R. and Dunwiddie, Thomas V. and Labarca, Cesar and Lester, Henry A. (1999) Allosteric Control of Gating and Kinetics at P2X₄ Receptor Channels. Journal of Neuroscience, 19 (17). pp. 7289-7299. ISSN 0270-6474. PMCID PMC6782529. doi:10.1523/jneurosci.19-17-07289.1999.

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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/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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1999 Society for Neuroscience. Received April 5, 1999; revised June 1, 1999; accepted June 14, 1999. This work was supported by a Wellcome Trust (UK) International Prize Fellowship (to B.S.K.), National Institutes of Health Grant NS-11756 and NS-29173, and grants from the Department of Veterans Affairs. Thanks to Dr. I Chessell (Glaxo Wellcome) for providing P2X cDNA clones and Dr. Phillipe Seguela for the P2X6 cDNA. We thank S. McKinney and H. Li for help with preparation of hippocampal cultures and Xenopus oocytes and W. B. Smith for guidance on use of the Biolistics gene gun.
Funding AgencyGrant Number
Department of Veterans AffairsUNSPECIFIED
Subject Keywords:ATP; ivermectin; ion channel; allosteric; modulation; P2X; purinoceptor
Issue or Number:17
PubMed Central ID:PMC6782529
Record Number:CaltechAUTHORS:20191028-115507054
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Official Citation:Allosteric Control of Gating and Kinetics at P2X4 Receptor Channels. Baljit S. Khakh, William R. Proctor, Thomas V. Dunwiddie, Cesar Labarca, Henry A. Lester. Journal of Neuroscience 1 September 1999, 19 (17) 7289-7299; DOI: 10.1523/JNEUROSCI.19-17-07289.1999
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99490
Deposited By: Tony Diaz
Deposited On:28 Oct 2019 20:17
Last Modified:16 Nov 2021 17:47

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