GABA receptor associated protein changes the electrostatic environment around the GABA type A receptor
Benedict W J Irwin1, Clara C Wanjura1, Daniel Molnar1
1Theory of Condensed Matter Group, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK.
Proteins
|September 21, 2021
Summary
The GABAA receptor associated protein (GABARAP) binding enhances chloride ion conductivity. Molecular dynamics simulations show GABARAP increases ion flow and receptor conductivity, aligning with experimental findings.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- The gamma-aminobutyric acid type A (GABAA) receptor is a crucial inhibitory neurotransmitter receptor in the central nervous system.
- GABA receptor associated protein (GABARAP) is known to interact with GABAA receptors, but its precise functional role remains incompletely understood.
Purpose of the Study:
- To investigate the impact of GABARAP binding on the structural and electrostatic properties of the GABAA receptor intracellular domain.
- To elucidate the effect of GABARAP on chloride ion permeation and channel gating dynamics.
Main Methods:
- Fully atomistic molecular dynamics (MD) simulations were employed to model the GABAA receptor intracellular domain.
- Electrostatic potential calculations were performed in the presence and absence of GABARAP.
- Analysis of ion trajectories and motions to assess conductivity and gating events.
Main Results:
- GABARAP binding significantly alters the electrostatic potential landscape surrounding the GABAA receptor.
- A notable increase in chloride ion conductivity through the receptor was observed upon GABARAP binding.
- Ion motions conducive to conducting currents occurred approximately twice as frequently with GABARAP bound.
Conclusions:
- GABARAP plays a critical role in modulating GABAA receptor function by influencing its electrostatic environment.
- The findings suggest that GABARAP enhances chloride ion flux, potentially by promoting channel opening or stabilizing conductive states.
- These computational results provide a molecular basis for experimental observations and highlight GABARAP as a key regulator of GABAergic signaling.
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