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Article

Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity

1
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA
2
Department of Anesthesia, Beckman Program for Molecular and Genetic Medicine, Stanford University, Stanford University Medical Center, Stanford, CA 94305, USA
3
Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(7), 2471; https://doi.org/10.3390/ijms21072471
Received: 4 March 2020 / Revised: 28 March 2020 / Accepted: 31 March 2020 / Published: 2 April 2020
(This article belongs to the Special Issue Purinergic P2 Receptors: Structure and Function)
Mouse models of alcohol use disorder (AUD) revealed purinergic P2X4 receptors (P2X4Rs) as a promising target for AUD drug development. We have previously demonstrated that residues at the transmembrane (TM)–ectodomain interface and within the TM1 segment contribute to the formation of an ethanol action pocket in P2X4Rs. In the present study, we tested the hypothesis that there are more residues in TM1 and TM2 segments that are important for the ethanol sensitivity of P2X4Rs. Using site-directed mutagenesis and two electrode voltage-clamp electrophysiology in Xenopus oocytes, we found that arginine at position 33 (R33) in the TM1 segment plays a role in the ethanol sensitivity of P2X4Rs. Molecular models in both closed and open states provided evidence for interactions between R33 and aspartic acid at position 354 (D354) of the neighboring TM2 segment. The loss of ethanol sensitivity in mixtures of wild-type (WT) and reciprocal single mutants, R33D:WT and D354R:WT, versus the WT-like response in R33D-D354R:WT double mutant provided further support for this interaction. Additional findings indicated that valine at TM1 position 49 plays a role in P2X4R function by providing flexibility/stability during channel opening. Collectively, these findings identified new activity sites and suggest the importance of TM1-TM2 interaction for the function and ethanol sensitivity of P2X4Rs. View Full-Text
Keywords: purinergic (P2X4) receptor; TM1 and TM2 segments; ethanol and agonist action; mutagenesis; molecular model purinergic (P2X4) receptor; TM1 and TM2 segments; ethanol and agonist action; mutagenesis; molecular model
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MDPI and ACS Style

Popova, M.; Rodriguez, L.; Trudell, J.R.; Nguyen, S.; Bloomfield, M.; Davies, D.L.; Asatryan, L. Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity. Int. J. Mol. Sci. 2020, 21, 2471. https://doi.org/10.3390/ijms21072471

AMA Style

Popova M, Rodriguez L, Trudell JR, Nguyen S, Bloomfield M, Davies DL, Asatryan L. Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity. International Journal of Molecular Sciences. 2020; 21(7):2471. https://doi.org/10.3390/ijms21072471

Chicago/Turabian Style

Popova, Maya, Larry Rodriguez, James R. Trudell, Sylvia Nguyen, Michael Bloomfield, Daryl L. Davies, and Liana Asatryan. 2020. "Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity" International Journal of Molecular Sciences 21, no. 7: 2471. https://doi.org/10.3390/ijms21072471

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