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Site and outcomes of lynx1 allosteric modulation of α3β4-nicotinic receptors with relevance to nicotine use disorder

Award Number: F31DA065413
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Site and outcomes of lynx1 allosteric modulation of α3β4-nicotinic receptors with relevance to nicotine use disorder - PROJECT SUMMARY Smoking is the leading cause of preventable death in the US and worldwide, and is maintained by nicotine- seeking behaviors, in part through the avoidance of withdrawal symptoms. Although combustible tobacco products have declined in popularity in recent years, the use of electronic nicotine delivery systems (ENDS) has skyrocketed and possesses its own set of health detriments. In the central nervous system nicotine acts on α3β4-nicotinic acetylcholine receptors (nAChR) which are expressed on GAD1+/SSt+ neurons of the interpeduncular nucleus (IPN). During nicotine cessation, activity of α3β4-nAChR on these neurons is diminished, releasing a critical brake on somatic withdrawal signaling. The prototoxin lynx1 is a negative allosteric modulator of α3β4-nAChR, and it is co-expressed with α3β4-nAChR in GAD1+/SSt+ IPN neurons. However, two critical issues remain unresolved. 1) The site and mechanism through which lynx1 exerts its effects as a negative allosteric modulator are not known. 2) Although the modulating effects of lynx1 on α3β4- nAChR function have been shown in heterologous expression systems, they have not yet been demonstrated to influence withdrawal behavior in a whole-animal model. To address the first open question, my Preliminary Data support the hypothesis that lynx1 binds preferentially to a site formed at the interface between two adjacent α3 subunits (α3/α3 interface). This interface is unique to only one isoform of α3β4-nAChR. Further, my Preliminary Data indicate that this α3/α3 interface may also bind agonists (itself a new discovery), and that this may result in competition between lynx1 and agonist binding at the α3/α3 interface. In Aim 1 of this fellowship I propose to use saturation and competition binding assays at heterologously expressed α3β4- nAChR to probe these possibilities directly. To address the second unresolved question, I propose to examine the relationship between lynx1 and somatic withdrawal symptoms in mice using nicotine minipumps to induce dependence. To emulate use of ENDS in a mouse model, this Aim also proposes to use a novel nicotine vapor inhalation paradigm, developed in the laboratory of my cosponsor. Both will be used to assess how the genetic deletion of lynx1 influences the severity of somatic withdrawal. Lynx1's effect on diminishing α3β4-mediated signaling is well-established by us and others. Decreased activity of the GAD1+/SSt+ neurons where lynx1 and α3β4-nAChR around found is associated with increased somatic withdrawal. Therefore we expect to observe decreased withdrawal signs in lynx1 KO mice vs. their WT counterparts (due to increased activity of the GAD1+/SSt+ neurons that inhibit withdrawal signaling). This behavioral Aim 2 will help uncover lynx1's contribution to producing nicotine withdrawal symptoms. Completion of this project will remove significant scientific barriers that impede the understanding of lynx1's site and mechanism of action at nAChRs, and its role in nicotine use disorder (NUD) and withdrawal signaling. This knowledge will provide a firm foundation for future work in development of improved NUD therapies.


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: 2026 ( Subtotal = $50,114 )
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	000	1	2/17/2026	NEW	$49,538
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	001	1	3/25/2026	NEW	$576
2026	2026	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Use and Addiction Research Programs	002	1	3/25/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Site and outcomes of lynx1 allosteric modulation of α3β4-nicotinic receptors with relevance to nicotine use disorder

Award Number: F31DA065413

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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