Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor.

ACS Chemical Neuroscience
Fabio LolicatoTomasz Róg

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 demonstra...Continue Reading

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Citations

Dec 18, 2020·Frontiers in Molecular Biosciences·Alex Bunker, Tomasz Róg
Nov 5, 2021·Langmuir : the ACS Journal of Surfaces and Colloids·Anand Kumar Sahu, Ashok Kumar Mishra

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Methods Mentioned

BETA
isothermal titration calorimetry

Software Mentioned

RAMD
CGneFF
wham
MODELER
Voro
GOLD
GROMACS
CHARMM36
APL
CHARMM

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