Membrane-dependent binding and entry mechanism of dopamine into its receptor
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 dif...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 15, 2020
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| In: |
ACS chemical neuroscience
Year: 2020, Volume: 11, Issue: 13, Pages: 1914-1924 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.9b00656 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acschemneuro.9b00656
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| Author Notes: | Fabio Lolicato, Hanna Juhola, Agata Zak, Pekka A. Postila, Annina Saukko, Sami Rissanen, Giray Enkavi, Ilpo Vattulainen, Mariusz Kepczynski, and Tomasz Róg |
| Summary: | 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. |
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| Item Description: | Gesehen am 17.09.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.9b00656 |