STRUCTURE AND BIOPHYSICS OF THE ACETYLCHOLINE RECEPTOR

Project: Research project

Project Details

Description

Central to communication in the nervous system are responses of
postsynaptic receptors to nerve-released transmitter. The proposed
research will explore how agonist binding triggers activation and
desensitization of the nicotinic acetylcholine receptor (AChR) found at
motor synapses. To examine these triggering processes, functionally
important regions will be identified by expressing in AChR complexes
subunits with genetically engineered mutations.

The first set of experiments will identify residues of the gamma and
delta subunits that contribute to the agonist binding sites. These
studies build upon recent evidence that the binding sites are formed at
interfaces between alpha and non-alpha subunits.

The second set of experiments will identify residues that couple
allosteric interactions between subunits in the pentamer. These studies
will bring new insights into how subunit interactions maintain the AChR
in the low affinity activatable state, as well as how such interactions
cooperatively link the two agonist binding sites.

Two final sets of experiments will identify parts of the AChR that couple
binding to channel opening. The first set will identify what AChR
subunits determine channel gating kinetics, while the second will
identify residues of the gamma and epsilon subunits that determine fetal
and adult gating kinetics.

Knowing how agonist binding triggers activation and desensitization is
essential to understanding AChR function, which in turn is essential to
understanding synaptic transmission and drug action at motor endplates.
The insights gained may provide similar insights for the entire
superfamily of neurotransmitter-gated ion channels.
StatusFinished
Effective start/end date9/1/924/30/18

ASJC

  • Medicine(all)
  • Neuroscience(all)