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Human adipose glycerol flux is regulated by a pH gate in AQP10.

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Gotfryd K, Mósca AF, Missel JW, Truelsen SF, Wang K, Spulber M, Krabbe S, Hélix-Nielsen C, Laforenza U, Soveral G, Pedersen PA, Gourdon P
OpenAccess logo Nat Commun 9 4749 (2018)
Cited: 58 times
EuropePMC logo PMID: 30420639

Abstract

Obesity is a major threat to global health and metabolically associated with glycerol homeostasis. Here we demonstrate that in human adipocytes, the decreased pH observed during lipolysis (fat burning) correlates with increased glycerol release and stimulation of aquaglyceroporin AQP10. The crystal structure of human AQP10 determined at 2.3 Å resolution unveils the molecular basis for pH modulation-an exceptionally wide selectivity (ar/R) filter and a unique cytoplasmic gate. Structural and functional (in vitro and in vivo) analyses disclose a glycerol-specific pH-dependence and pinpoint pore-lining His80 as the pH-sensor. Molecular dynamics simulations indicate how gate opening is achieved. These findings unravel a unique type of aquaporin regulation important for controlling body fat mass. Thus, targeting the cytoplasmic gate to induce constitutive glycerol secretion may offer an attractive option for treating obesity and related complications.

Reviews - 6f7h mentioned but not cited (4)

  1. Inhibitors of Mammalian Aquaporin Water Channels. Abir-Awan M, Kitchen P, Salman MM, Conner MT, Conner AC, Bill RM. Int J Mol Sci 20 E1589 (2019)
  2. Aquaporins in insulin resistance and diabetes: More than channels! Galli M, Hameed A, Żbikowski A, Zabielski P. Redox Biol 44 102027 (2021)
  3. Aquaporin Gating: A New Twist to Unravel Permeation through Water Channels. Ozu M, Alvear-Arias JJ, Fernandez M, Caviglia A, Peña-Pichicoi A, Carrillo C, Carmona E, Otero-Gonzalez A, Garate JA, Amodeo G, Gonzalez C. Int J Mol Sci 23 12317 (2022)
  4. Folding and Insertion of Transmembrane Helices at the ER. Whitley P, Grau B, Gumbart JC, Martínez-Gil L, Mingarro I. Int J Mol Sci 22 12778 (2021)

Articles - 6f7h mentioned but not cited (12)



Reviews citing this publication (13)

  1. Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease. Wagner K, Unger L, Salman MM, Kitchen P, Bill RM, Yool AJ. Int J Mol Sci 23 1388 (2022)
  2. Molecular mechanisms governing aquaporin relocalisation. Markou A, Unger L, Abir-Awan M, Saadallah A, Halsey A, Balklava Z, Conner M, Törnroth-Horsefield S, Greenhill SD, Conner A, Bill RM, Salman MM, Kitchen P. Biochim Biophys Acta Biomembr 1864 183853 (2022)
  3. Phosphorylation-Dependent Regulation of Mammalian Aquaporins. Nesverova V, Törnroth-Horsefield S. Cells 8 E82 (2019)
  4. Aquaglyceroporin Modulators as Emergent Pharmacological Molecules for Human Diseases. Pimpão C, Wragg D, da Silva IV, Casini A, Soveral G. Front Mol Biosci 9 845237 (2022)
  5. Aquaporin ion conductance properties defined by membrane environment, protein structure, and cell physiology. Henderson SW, Nourmohammadi S, Ramesh SA, Yool AJ. Biophys Rev 14 181-198 (2022)
  6. Prokaryotic Aquaporins. Tong H, Hu Q, Zhu L, Dong X. Cells 8 E1316 (2019)
  7. Endothelial Dysfunction in Neurodegenerative Diseases. Fang YC, Hsieh YC, Hu CJ, Tu YK. Int J Mol Sci 24 2909 (2023)
  8. Aquaporins: New players in breast cancer progression and treatment response. Charlestin V, Fulkerson D, Arias Matus CE, Walker ZT, Carthy K, Littlepage LE. Front Oncol 12 988119 (2022)
  9. Aquaporins and Ion Channels as Dual Targets in the Design of Novel Glioblastoma Therapeutics to Limit Invasiveness. Varricchio A, Yool AJ. Cancers (Basel) 15 849 (2023)
  10. Cooperativity in regulation of membrane protein function: phenomenological analysis of the effects of pH and phospholipids. Zerbetto De Palma G, Recoulat Angelini AA, Vitali V, González Flecha FL, Alleva K. Biophys Rev 15 721-731 (2023)
  11. Structure and function of a silicic acid channel Lsi1. Saitoh Y, Suga M. Front Plant Sci 13 982068 (2022)
  12. Aquaporins Display a Diversity in their Substrates. Sachdeva R, Priyadarshini P, Gupta S. J Membr Biol 256 1-23 (2023)
  13. Mechanosensitive aquaporins. Ozu M, Galizia L, Alvear-Arias JJ, Fernández M, Caviglia A, Zimmermann R, Guastaferri F, Espinoza-Muñoz N, Sutka M, Sigaut L, Pietrasanta LI, González C, Amodeo G, Garate JA. Biophys Rev 15 497-513 (2023)

Articles citing this publication (29)



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