Membrane-dependent binding and entry mechanism of dopamine into its receptor

• Verfasst von: Lolicato, Fabio [VerfasserIn]
• Verfasst von: Juhola, Hanna [VerfasserIn]
• Verfasst von: Zak, Agata [VerfasserIn]
• Verfasst von: Postila, Pekka A. [VerfasserIn]
• Verfasst von: Saukko, Annina [VerfasserIn]
• Verfasst von: Rissanen, Sami [VerfasserIn]
• Verfasst von: Enkavi, Giray [VerfasserIn]
• Verfasst von: Vattulainen, Ilpo [VerfasserIn]
• Verfasst von: Kepczynski, Mariusz [VerfasserIn]
• Verfasst von: Róg, Tomasz [VerfasserIn]
• Titel: Membrane-dependent binding and entry mechanism of dopamine into its receptor
• Verf.angabe: Fabio Lolicato, Hanna Juhola, Agata Zak, Pekka A. Postila, Annina Saukko, Sami Rissanen, Giray Enkavi, Ilpo Vattulainen, Mariusz Kepczynski, and Tomasz Róg
• E-Jahr: 2020
• Jahr: June 15, 2020
• Umfang: 11 S.
• Fussnoten: Gesehen am 17.09.2020
• Titel Quelle: Enthalten in: American Chemical SocietyACS chemical neuroscience
• Ort Quelle: Washington, DC : ACS Publ., 2010
• Jahr Quelle: 2020
• Band/Heft Quelle: 11(2020), 13, Seite 1914-1924
• ISSN Quelle: 1948-7193
• DOI: doi:10.1021/acschemneuro.9b00656
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1733194908

Abstract

Synaptic neurotransmission has recently been proposed to function via either a membrane-independent or a membrane-dependent mechanism, depending on the neurotransmitter type. In the membrane-dependent mechanism, amphipathic neurotransmitters first partition to the lipid headgroup region and then diffuse along the membrane plane to their membrane-buried receptors. However, to date, this mechanism has not been demonstrated for any neurotransmitter-receptor complex. Here, we combined isothermal calorimetry measurements with a diverse set of molecular dynamics simulation methods to investigate the partitioning of an amphipathic neurotransmitter (dopamine) and the mechanism of its entry into the ligand-binding site. Our results show that the binding of dopamine to its receptor is consistent with the membrane-dependent binding and entry mechanism. Both experimental and simulation results showed that dopamine favors binding to lipid membranes especially in the headgroup region. Moreover, our simulations revealed a ligand-entry pathway from the membrane to the binding site. This pathway passes through a lateral gate between transmembrane alpha-helices 5 and 6 on the membrane-facing side of the protein. All in all, our results demonstrate that dopamine binds to its receptor by a membrane-dependent mechanism, and this is complemented by the more traditional binding mechanism directly through the aqueous phase. The results suggest that the membrane-dependent mechanism is common in other synaptic receptors, too.