Investigation of two interacting neurosteroid sites on a GABA receptor by mutagenesis and mathematical modeling
Year: 2012
Type: article
Abstract: residue known for involvement in enhancement of GABA receptors by many modulators.We mathematically modeled the data to attribute the change in modulation caused by the mutation solely to a change in enhancement.The experiment was performed on multiple receptor chimeras to confirm wider applicability of the model.Because M2 15' is known as an enhancing residue, we predict that changes in modulation will be attributable solely to increased activity of the enhancement pathway, thus confirming that enhancement is operating independently of and simultaneously with inhibition.Receptors showed decreased inhibition and/or increased enhancement when exposed to the neurosteroids consistent with multiple pathways occurring.However, unexpectedly, the mutations to the enhancement pathway also affected the activity of the inhibition pathway.These data suggest M2 15' is not involved solely in enhancement and may be involved in neurosteroid inhibition.This reveals a new function for well-studied M2 15' as a residue involved in both inhibition and enhancement.In addition, modeling suggests that the neurosteroid directly affects the gating process rather than affecting the process that occurs between ligand binding and channel opening.This narrows down the set of receptor conformational changes that may be allosterically inhibited by neurosteroids.This contributes to an expanded understanding of the allosteric regulatory pathways of GABA receptors and has provided a lead-in toward drug development by adding to the characterization of a potentially useful site for the development of novel pesticides.
Author: Lindsay A. Horn
Institution: University of Toledo
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1658030774