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Expression of Mutant Glycine Receptors in Xenopus Oocytes Using Canonical and Non-Canonical Amino Acids Reveals Distinct Roles of Conserved Proline Residues

Lummis, Sarah C. R. and Dougherty, Dennis A. (2022) Expression of Mutant Glycine Receptors in Xenopus Oocytes Using Canonical and Non-Canonical Amino Acids Reveals Distinct Roles of Conserved Proline Residues. Membranes, 12 (10). Art. No. 1012. ISSN 2077-0375. PMCID PMC9607081. doi:10.3390/membranes12101012. https://resolver.caltech.edu/CaltechAUTHORS:20221110-429809700.2

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Abstract

Pentameric ligand-gated ion channels (pLGIC) play important roles in fast neuronal signal transmission. Functional receptors are pentamers, with each subunit having an extracellular domain (ECD), a transmembrane domain (TMD) and an intracellular domain. The binding of the agonist to the ECD induces a structural change that is transduced to the TMD to open the channel. Molecular details of this process are emerging, but a comprehensive understanding is still lacking. Proline (Pro) is one amino acid that has attracted much interest; its unusual features generate bends in loops and kinks and bulges in helices, which can be essential for function in some pLGICs. Here, we explore the roles of four conserved Pros in the glycine receptor (GlyR), creating substitutions with canonical and noncanonical amino acids, characterizing them using two electrode voltage clamp electrophysiology in Xenopus oocytes, and interpreting changes in receptor parameters using structural data from the open and closed states of the receptor. The data reveal that for efficient function, the Pro in the α1β1 loop is needed to create a turn and to be the correct size and shape to interact with nearby residues; the peptide bond of the Pro in the Cys-loop requires the cis conformation; and the Pros in loop A and M1 allow efficient function because of their reduced hydrogen bonding capacity. These data are broadly consistent with data from other pLGICs, and therefore likely represent the important features of these Pros in all members of the family.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.3390/membranes12101012DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9607081PubMed CentralArticle
ORCID:
AuthorORCID
Lummis, Sarah C. R.0000-0001-9410-9805
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:DAD was supported by the National Institute of Health grant NS-34407. SCRL was supported by the Medical Research Council grant MR/L021676/1.
Funders:
Funding AgencyGrant Number
NIHNS-34407
Medical Research Council (UK)MR/L021676/1
Issue or Number:10
PubMed Central ID:PMC9607081
DOI:10.3390/membranes12101012
Record Number:CaltechAUTHORS:20221110-429809700.2
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20221110-429809700.2
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:117819
Collection:CaltechAUTHORS
Deposited By: Research Services Depository
Deposited On:27 Nov 2022 20:45
Last Modified:28 Nov 2022 17:55

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