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5-HT3 Receptor MX Helix Contributes to Receptor Function.
James Mocatta1, Susanne M Mesoy1, Dennis A Dougherty2
1Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
ACS Chemical Neuroscience
|July 22, 2022
Summary
The MX helix in serotonin 5-HT3 receptors influences channel function and assembly. Interactions with membrane lipids are key to its role in receptor gating and opening.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Serotonin 5-HT3 receptors are pentameric ligand-gated ion channels crucial for neurotransmission.
- The intracellular domain's MX helix is structurally distinct in open and closed states, suggesting a functional role.
Purpose of the Study:
- To investigate the functional significance of the MX helix in 5-HT3 receptor gating and assembly.
- To explore the role of lipid-protein interactions involving the MX helix.
Main Methods:
- Alanine substitution mutagenesis of MX helix residues.
- Functional characterization of mutant receptors in HEK293 cells.
- Radiolabeled ligand binding assays.
- Molecular dynamics simulations.
Main Results:
- Mutations in the MX helix modulated EC50 values, indicating altered gating, while binding affinity remained unchanged.
- Several mutations impaired receptor function, suggesting roles in assembly or folding, rescued by chaperone coexpression.
- MD simulations indicated differential lipid interactions with the MX helix in open versus closed states.
Conclusions:
- The MX helix acts as a modulator of 5-HT3 receptor function.
- Lipid interactions with the MX helix are proposed to significantly influence channel opening propensity.
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