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Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP.
Elife 2019; 8E

Abstract

P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca2+-ATP and Mg2+-ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development.

Authors+Show Affiliations

Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Multiscale Research Institute for Complex Systems, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Multiscale Research Institute for Complex Systems, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31232692

Citation

Li, Mufeng, et al. "Molecular Mechanisms of Human P2X3 Receptor Channel Activation and Modulation By Divalent Cation Bound ATP." ELife, vol. 8, 2019.
Li M, Wang Y, Banerjee R, et al. Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. Elife. 2019;8.
Li, M., Wang, Y., Banerjee, R., Marinelli, F., Silberberg, S., Faraldo-Gómez, J. D., ... Swartz, K. J. (2019). Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. ELife, 8, doi:10.7554/eLife.47060.
Li M, et al. Molecular Mechanisms of Human P2X3 Receptor Channel Activation and Modulation By Divalent Cation Bound ATP. Elife. 2019 Jun 24;8 PubMed PMID: 31232692.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP. AU - Li,Mufeng, AU - Wang,Yao, AU - Banerjee,Rahul, AU - Marinelli,Fabrizio, AU - Silberberg,Shai, AU - Faraldo-Gómez,José D, AU - Hattori,Motoyuki, AU - Swartz,Kenton Jon, Y1 - 2019/06/24/ PY - 2019/03/21/received PY - 2019/06/06/accepted PY - 2019/6/25/entrez PY - 2019/6/25/pubmed PY - 2019/6/25/medline KW - Ca binding sites KW - Mg binding sites KW - Mg-ATP KW - divalent cations KW - forms of ATP KW - human KW - molecular biophysics KW - structural biology JF - eLife JO - Elife VL - 8 N2 - P2X3 receptor channels expressed in sensory neurons are activated by extracellular ATP and serve important roles in nociception and sensory hypersensitization, making them attractive therapeutic targets. Although several P2X3 structures are known, it is unclear how physiologically abundant Ca2+-ATP and Mg2+-ATP activate the receptor, or how divalent cations regulate channel function. We used structural, computational and functional approaches to show that a crucial acidic chamber near the nucleotide-binding pocket in human P2X3 receptors accommodates divalent ions in two distinct modes in the absence and presence of nucleotide. The unusual engagement between the receptor, divalent ion and the γ-phosphate of ATP enables channel activation by ATP-divalent complex, cooperatively stabilizes the nucleotide on the receptor to slow ATP unbinding and recovery from desensitization, a key mechanism for limiting channel activity. These findings reveal how P2X3 receptors recognize and are activated by divalent-bound ATP, aiding future physiological investigations and drug development. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/31232692/Molecular_mechanisms_of_human_P2X3_receptor_channel_activation_and_modulation_by_divalent_cation_bound_ATP L2 - https://doi.org/10.7554/eLife.47060 DB - PRIME DP - Unbound Medicine ER -