Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic "OR" Gate Based on the Glycine Receptor.

Abstract:

:The glycine receptor (GlyR) is a ligand-activated chloride channel, whose mutations are the major cause of hereditary hyperekplexia. The hyperekplexia-causing R271Q mutation, which is located at the extracellular outer mouth of the channel pore, dramatically impairs the GlyR function manifesting a reduced sensitivity toward glycine. This study reports that a second mutation, S273D, rescues the function of the R271Q GlyR to that of the wild-type (WT) GlyR. Surprisingly, the S273D mutation, when introduced to the WT GlyR, does not further increase the receptor function. In other words, the compromised function of the 271Q 273S GlyR (i.e., the R271Q GlyR) can be rescued to WT levels by the introduction of either, or both, of the Q271R and S273D substitutions. From the perspective of Boolean logic gates, the Q271R and S273D substitutions act as inputs for an OR gate based on the GlyR. Further experiments revealed that the negative-charge carried by the 273 residue is essential for the expression of the OR gate and that the expression of the OR gate is residue-position-specific. In addition, mechanistic investigation implied that the 273 residue influences the 271 residue, which might underpin the unique nonadditive OR gate relationship between these two residues. Such an ion-channel-based OR gate, expressing output in the form of electrical current, could potentially be developed to digitally manipulate neuronal activity.

journal_name

ACS Chem Neurosci

authors

Han L,Shan Q

doi

10.1021/acschemneuro.0c00522

subject

Has Abstract

pub_date

2020-10-21 00:00:00

pages

3409-3417

issue

20

issn

1948-7193

journal_volume

11

pub_type

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