OSCR

An accessory orthosteric ligand binding site in the (α3)<sub>3</sub>(β4)<sub>2</sub> nicotinic acetylcholine receptor regulates channel activation.

Overview

Authors: Gauri C. Kulkarni1,2, Megan J. Jurek1,3, Andrew P. Riley1,3, Christian J. Peters1,2,3,4,5
ORCID iDs: Megan J. Jurek, Christian J. Peters
  1. University of Illinois Chicago, Chicago, IL 60612, USA
  2. Department of Anatomy & Cell Biology, University of Illinois Chicago, Chicago, IL 60612, USA
  3. Department of Pharmaceutical Sciences, University of Illinois Chicago, Chicago, IL 60612, USA
  4. Senior author
  5. Lead contact
Institutions: University of Illinois Chicago (United States)
Journal: Cell reports, volume 45, issue 4, article 117077
Dates: published online 20 March 2026; in print March 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1016/j.celrep.2026.117077 · PMID 41865374 · PMCID PMC13191732 · OpenAlex W7139955601
Open access: gold, a free copy (OpenAlex)
Status: code on request (how the code is found and verified)
Categories: cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: Acetylcholine, Electrophysiology, Nicotinic acetylcholine receptor, Mtset, Cp: Neuroscience, Cp: Cell Biology, Accessory Orthosteric Binding Site, Receptor Stoichiometry, Α3β4 Receptors
Topic: Nicotinic Acetylcholine Receptors Study (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Institute on Drug Abuse (R01DA057961, R00DA041500); NIDA NIH HHS (R00 DA041500); NINDS NIH HHS (R01 NS134647); National Institutes of Health
Citations: not cited yet (Europe PMC); 45 references in the paper
Research resources: Human: HEK293T RRID:CVCL_0045

Abstract

The α3β4 nicotinic acetylcholine receptor (nAChR) is a heteropentameric ligand-gated channel whose distribution includes reward circuits of the brain, where it regulates expression of drug withdrawal symptoms. α3β4 nAChRs form two stoichiometries in the absence of other subunits, containing orthosteric binding sites between the primary α3 and the adjacent β4 subunit. The identity of the fifth (accessory) subunit is different between the two stoichiometries, but it is unknown whether this structural nuance yields any biophysical differences. To investigate this, we constrained receptor stoichiometry by engineering an α3β4 tandem dimer and co-expressing it in HEK293T cells with a select fifth subunit. We then used substituted-cysteine accessibility to covalently modify the primary and accessory binding sites. This approach revealed a functional “accessory orthosteric” site at the α3-α3 interface of (α3)3(β4)2 nAChRs. Understanding the stoichiometric differences in α3β4 nAChRs will inform future therapeutic strategies to target nicotine withdrawal.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

No dataset and no data link were found in the paper.

Data and code availability

Data reported in this paper have been deposited at Figshare and are publicly available at https://doi.org/10.25417/uic.31244980.

This paper does not report original code.

Any additional information reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 4 authors, 9 keywords, 4 funders, 45 references, 1 RRID.

Cite

This paper

Kulkarni, G. C., Jurek, M. J., Riley, A. P., & Peters, C. J. (2026). An accessory orthosteric ligand binding site in the (α3)<sub>3</sub>(β4)<sub>2</sub> nicotinic acetylcholine receptor regulates channel activation. Cell reports, 45(4), 117077. https://doi.org/10.1016/j.celrep.2026.117077

BibTeX

@article{kulkarni2026accessory,
author = {Kulkarni, Gauri C. and Jurek, Megan J. and Riley, Andrew P. and Peters, Christian J.},
title = {{An accessory orthosteric ligand binding site in the (α3)\<sub\>3\</sub\>(β4)\<sub\>2\</sub\> nicotinic acetylcholine receptor regulates channel activation}},
journal = {Cell reports},
year = {2026},
month = mar,
volume = {45},
number = {4},
pages = {117077},
publisher = {Cell Press},
issn = {2211-1247},
doi = {10.1016/j.celrep.2026.117077},
url = {https://doi.org/10.1016/j.celrep.2026.117077},
pmid = {41865374},
pmcid = {PMC13191732}
}

RIS

TY - JOUR
AU - Kulkarni, Gauri C.
AU - Jurek, Megan J.
AU - Riley, Andrew P.
AU - Peters, Christian J.
TI - An accessory orthosteric ligand binding site in the (α3)<sub>3</sub>(β4)<sub>2</sub> nicotinic acetylcholine receptor regulates channel activation
T2 - Cell reports
J2 - Cell Rep
PY - 2026
DA - 2026/03/20
VL - 45
IS - 4
SP - 117077
SN - 2211-1247
PB - Cell Press
DO - 10.1016/j.celrep.2026.117077
UR - https://doi.org/10.1016/j.celrep.2026.117077
LA - en
ER -

CSL-JSON

{
"id": "10.1016/j.celrep.2026.117077",
"type": "article-journal",
"title": "An accessory orthosteric ligand binding site in the (α3)<sub>3</sub>(β4)<sub>2</sub> nicotinic acetylcholine receptor regulates channel activation",
"container-title": "Cell reports",
"author": [
{
"family": "Kulkarni",
"given": "Gauri C."
},
{
"family": "Jurek",
"given": "Megan J."
},
{
"family": "Riley",
"given": "Andrew P."
},
{
"family": "Peters",
"given": "Christian J."
}
],
"container-title-short": "Cell Rep",
"volume": "45",
"issue": "4",
"page": "117077",
"DOI": "10.1016/j.celrep.2026.117077",
"PMID": "41865374",
"PMCID": "PMC13191732",
"ISSN": "2211-1247",
"publisher": "Cell Press",
"URL": "https://doi.org/10.1016/j.celrep.2026.117077",
"language": "en",
"issued": {
"date-parts": [
[
2026,
3,
20
]
]
}
}

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1038/s41467-025-58333-0
Molecular insights into the α6β4 nicotinic acetylcholine receptor function and ligand recognition.
Journal: Nature communications
In common: cellular / molecular, 3 references
[2] doi:10.1038/s44318-024-00165-7
Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.
Journal: The EMBO journal
In common: cellular / molecular, 2 references
[3] doi:10.3390/cells14050340
The Cholinergic Receptor Nicotinic α3 Was Reduced in the Hippocampus of Early Cognitively Impaired Adult Male Mice and Upregulated by Nicotine and Cytisine in HT22 Cells.
Journal: Cells
In common: cellular / molecular, 1 reference
[4] doi:10.1038/s41467-022-35346-7 [code]
Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion.
Journal: Nature communications
In common: cellular / molecular, 1 reference
[5] doi:10.1016/j.isci.2024.111646
FOXP2-immunoreactive corticothalamic neurons in neocortical layers 6a and 6b are tightly regulated by neuromodulatory systems.
Journal: iScience
In common: cellular / molecular, 1 reference
[6] doi:10.1038/s41467-024-51904-7
Divergent mechanisms of steroid inhibition in the human ρ1 GABA<sub>A</sub> receptor.
Journal: Nature communications
In common: cellular / molecular, 1 reference
[7] doi:10.15252/embj.2023115030
Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.
Journal: The EMBO journal
In common: cellular / molecular, 1 reference
[8] doi:10.1016/j.isci.2023.105992
Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons.
Journal: iScience
In common: cellular / molecular, 1 reference
[9] doi:10.1038/s41467-026-74279-3
Structural basis for activation and potentiation in a human α5β3 GABA<sub>A</sub> receptor.
Journal: Nature communications
In common: cellular / molecular, 1 reference
[10] doi:10.1038/s41467-024-49471-y
Structural insights into GABA<sub>A</sub> receptor potentiation by Quaalude.
Journal: Nature communications
In common: cellular / molecular, 1 reference

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.