Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants

We
present a framework for computing the gating properties of ligand-gated
ion channel mutants using the Monod-Wyman-Changeux (MWC) model of
allostery. We derive simple analytic formulas for key functional properties
such as the leakiness, dynamic range, half-maximal effective concentration
([EC50]), and effective Hill coefficient, and explore the
full spectrum of phenotypes that are accessible through mutations.
Specifically, we consider mutations in the channel pore of nicotinic
acetylcholine receptor (nAChR) and the ligand binding domain of a
cyclic nucleotide-gated (CNG) ion channel, demonstrating how each
mutation can be characterized as only affecting a subset of the biophysical
parameters. In addition, we show how the unifying perspective offered
by the MWC model allows us, perhaps surprisingly, to collapse the
plethora of dose-response data from different classes of ion channels
into a universal family of curves.