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Molecular mechanisms of TARP modulation of AMPA receptor gating.

Award Number: R21NS146672
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: 01/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Molecular mechanisms of TARP modulation of AMPA receptor gating. - PROJECT SUMMARY AMPA receptors are critical components of excitatory synaptic transmission and play myriad roles in brain function. AMPA receptors are nearly always accompanied by one or more types of auxiliary proteins, principal among these being the transmembrane AMPA receptor regulatory proteins (TARPs). This family of four-pass transmembrane proteins contains prominent extracellular domains that interact with AMPA receptors to modulate channel gating. However, not all TARPs modulate AMPA receptors equally. For example, the TARP γ8 alters AMPA receptor kinetics to a greater extent than γ2 (a.k.a stargazin), even inducing a striking resensitization or superactivation response. Structural and functional studies implicate the large β1-2 extracellular loop of γ8 as critical for kinetic modulation. Consistent with this, swapping the larger β1-2 loop of γ8 with the smaller loop of γ2 can broadly exchange the modulatory phenotype. Because this β1-2 loop is flexible, it remains unresolved in cryo-EM structures. Thus, the precise contacts between the loop and the AMPA receptor, and the underlying mechanism of modulation, is unclear. Interestingly, focused refinement of the β1-2 loop indicates this segment may move between the resting, active, and desensitized states, potentially producing new contacts. Here we propose to identify contact sites between the γ2 or γ8 β1-2 loop and the AMPA receptor using a combination of non-canonical amino acid crosslinking and patch clamp fluorometry. In addition, we will use patch clamp FRET to discern if the β1-2 loops of γ2 or γ8 move during activation, desensitization, and superactivation. Taken together, these studies will advance our mechanistic understanding of AMPA receptor and TARP interactions and glutamate receptor gating. Furthermore, developing these techniques will allow us and others to interrogate the relative positions and ensemble movements of the many unresolved or intrinsically disordered regions of membrane proteins.


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 = $226,500 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/22/2025	NEW	$226,500
														Subtotal = $226,500

Grand Total All Awards = $226,500

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Molecular mechanisms of TARP modulation of AMPA receptor gating.

Award Number: R21NS146672

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: 01/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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