Thursday, July 3, 2025 7/3/2025

Probing the structure and function of the intracellular domain of cys-loop receptors

Award Number: R01NS077114
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

Group Awards By:

View Award Description

Probing the structure and function of the intracellular domain of cys-loop receptors - Project Summary Pentameric ligand-gated ion channels (pLGICs), also called Cys-loop receptors in eukaryotes, include the receptors for acetylcholine, serotonin, GABA and glycine. They are involved in numerous neuropsychiatric, neurologic, and inflammatory diseases. All Cys-loop receptor family members in metazoans contain three structural domains: an extracellular domain (ECD), a transmembrane domain (TMD), and an intracellular domain (ICD). The ECD and TMD are architecturally conserved between receptor families. The ICD is poorly conserved in both length and amino-acid composition and, for many subunits, contains large regions of predicted structural disorder. Due to the challenge of working with the ICDs of pentameric receptors, they have been essentially overlooked in terms of rigorous mechanistic characterization and direct exploration as pharmacological targets. The ICD is involved in finetuning plasma membrane expression levels, targeting, and function, in part mediated by protein-protein interactions (PPI) for example with chaperones. We envision that mechanistic knowledge of chaperone-mediated modulation will uncover new PPI drug targets. Through our published studies of the ICD we defined a linker that allowed for structure determination of the first in class structures of homo- and heteropentameric GABAA receptors. We also established that the ICD alone assembles into pentamers, establishing a novel role for the ICD in oligomeric assembly. Here, we propose a multi-layered approach leveraging both soluble ICD chimeras and full-length receptors together with results obtained during the previous funding period in careful consideration of recently-published pLGIC structures. We discovered that the resistance to inhibitors of choline esterase (Ric-3) chaperone binds to a 24-amino acid L1-MX segment of 5-HT3A subunits. With the new proposed specific aims (SA) we will: (SA1) determine the role of the L1-MX segment in RIC-3 modulation of cationic pLGIC assembly, (SA2) identify novel protein-protein interactions mediated via cationic ICDs, and (SA3) characterize the mechanism by which opening of cation-conducting pLGICs involves translocation of the L1-MX segment through the MA-helix framed portals. In each aim, we will use biochemical and electrophysiological methods, coupled with overexpressed and purified proteins or proteins in their cellular environment. We anticipate that our studies will provide the basis for a novel class of targets for therapeutic development, PPI modulators for pentameric channel intracellular domains.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $344,250 )
2025	2025	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	11/26/2024	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $344,250

Issue Date FY: 2024 ( Subtotal = $371,025 )
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/16/2023	NON-COMPETING CONTINUATION	$344,250
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/3/2024	NON-COMPETING CONTINUATION	$26,775
														Subtotal = $371,025

Issue Date FY: 2023 ( Subtotal = $498,890 )
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	11/30/2022	NON-COMPETING CONTINUATION	$344,250
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	2/1/2023	NON-COMPETING CONTINUATION	$38,250
2023	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/1/2022	COMPETING CONTINUATION	$116,390
														Subtotal = $498,890

Issue Date FY: 2022 ( Subtotal = $382,500 )
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/13/2021	COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2020 ( Subtotal = -$30 )
2020	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/8/2020	NON-COMPETING CONTINUATION	-$30
														Subtotal = -$30

Issue Date FY: 2018 ( Subtotal = $328,974 )
2018	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/25/2018	NON-COMPETING CONTINUATION	$32,898
2018	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST MS 6271	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/9/2018	NON-COMPETING CONTINUATION	$296,076
														Subtotal = $328,974

Issue Date FY: 2017 ( Subtotal = $328,974 )
2017	2017	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST MS 6271	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/15/2017	NON-COMPETING CONTINUATION	$296,076
2017	2017	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST MS 6271	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	5/26/2017	NON-COMPETING CONTINUATION	$32,898
														Subtotal = $328,974

Issue Date FY: 2016 ( Subtotal = $328,974 )
2016	2016	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/8/2016	NON-COMPETING CONTINUATION	$328,974
														Subtotal = $328,974

Issue Date FY: 2015 ( Subtotal = $328,974 )
2015	2015	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/10/2015	NON-COMPETING CONTINUATION	$328,974
														Subtotal = $328,974

Issue Date FY: 2014 ( Subtotal = $328,974 )
2014	2014	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/10/2014	NEW	$328,974
														Subtotal = $328,974

Grand Total All Awards = $3,241,505

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Probing the structure and function of the intracellular domain of cys-loop receptors

Award Number: R01NS077114

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer