Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/47060 |
| _version_ | 1818028466814058496 |
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| author | Mufeng Li Yao Wang Rahul Banerjee Fabrizio Marinelli Shai Silberberg José D Faraldo-Gómez Motoyuki Hattori Kenton Jon Swartz |
| author_facet | Mufeng Li Yao Wang Rahul Banerjee Fabrizio Marinelli Shai Silberberg José D Faraldo-Gómez Motoyuki Hattori Kenton Jon Swartz |
| author_sort | Mufeng Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:04:15Z |
| format | Article |
| id | doaj.art-8c9f3248dbf547e6b13d0827376b0951 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:04:15Z |
| publishDate | 2019-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8c9f3248dbf547e6b13d0827376b09512022-12-22T02:01:18ZengeLife Sciences Publications LtdeLife2050-084X2019-06-01810.7554/eLife.47060Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATPMufeng Li0Yao Wang1Rahul Banerjee2Fabrizio Marinelli3https://orcid.org/0000-0003-0044-6718Shai Silberberg4José D Faraldo-Gómez5https://orcid.org/0000-0001-7224-7676Motoyuki Hattori6https://orcid.org/0000-0002-5327-5337Kenton Jon Swartz7https://orcid.org/0000-0003-3419-0765Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesState 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, ChinaTheoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesTheoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesTheoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United StatesState 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, ChinaMolecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United StatesP2X3 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.https://elifesciences.org/articles/47060Mg-ATPdivalent cationsMg binding sitesCa binding sitesforms of ATP |
| spellingShingle | Mufeng Li Yao Wang Rahul Banerjee Fabrizio Marinelli Shai Silberberg José D Faraldo-Gómez Motoyuki Hattori Kenton Jon Swartz Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP eLife Mg-ATP divalent cations Mg binding sites Ca binding sites forms of ATP |
| title | Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP |
| title_full | Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP |
| title_fullStr | Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP |
| title_full_unstemmed | Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP |
| title_short | Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP |
| title_sort | molecular mechanisms of human p2x3 receptor channel activation and modulation by divalent cation bound atp |
| topic | Mg-ATP divalent cations Mg binding sites Ca binding sites forms of ATP |
| url | https://elifesciences.org/articles/47060 |
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