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Structural Dynamics in Rhodopsin Activation and Attenuation

Award Number: R01EY029343
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Structural Dynamics in Rhodopsin Activation and Attenuation - Project Summary A long-term goal of our research is to understand the molecular mechanisms through which G-protein coupled receptors (GPCRs) are activated and attenuated. GPCRs are the largest family in the human genome, and the target of most pharmaceutical drugs. One exception has been rhodopsin – although the first GPCR discovered, it has so far been refractory to direct pharmacological treatments. Here the Kliger and Farrens lab join forces to define the dynamic events and mechanisms involved in the photo-activation of human rhodopsin and cone photopsins, determine how rhodopsin interacts with its ligand, retinal, determine how its function changes with mutations responsible for retinal diseases and determine how these interactions enable, and are modulated by, interactions with its affiliate protein arrestin. Although the structures of retinal, rhodopsin, and arrestin are now known, the dynamic processes that enable them to interact with each other are not. Thus, the types of studies we propose here are required. Specific Aim 1 will determine the photoactivation kinetics of human red and green cone pigments, determine how the activation of human rhodopsin is short-circuited by mutations associated with ADRP, and test how these kinetics are effected by small molecule chaperones used to treat and stabilize misfolded opsins. Specific Aim 2 will determine what role novel receptor conformations play in the process of retinal uptake and release, test if a previously unidentified receptor conformation enables binding of 11-cis retinal (11CR), and expand on our discovery that opsin can transiently linger in an active-like state after releasing all-trans retinal (ATR). Finally, Specific Aim 3 will determine if arrestin binding enables ATR to bind photobleached rhodopsin in equilibrium, and define what effect arrestin binding to rhodopsin dimers has on this phenomenon. Understanding what regulates the process of rhodopsin photoactivation, and retinal uptake and release, and how arrestin regulates these actions is critically important from a health perspective. The retina must accommodate huge variations in these events as it adapts to widely different light conditions, yet aberrations in this process over time are thought to result in the formation of oxidative retinal adducts that promote diseases like atrophic age-related macular degeneration (AMD). Thus, it appears that arrestin must walk a fine line – on the one hand controlling the amount of free retinal released under varying light conditions, and on the other releasing retinal and itself from the receptor at the appropriate time to avoid forming stable rhodopsin-arrestin complexes that can contribute to apoptosis and some forms of retinitis pigmentosa. The work here complements our recent discovery that ATR can exchange in equilibrium with some rhodopsin photoproducts, and recent discoveries by others of non-retinal ligands that bind and stabilize misfolded opsins. These findings dramatically increase the possibility that drugs can be developed to either compete with or enhance retinal binding, thus opening the door for treating this key photoreceptor with pharmacological agents.


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 = $0 )
2026	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	5	11/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $520,978 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	6	5/30/2025	COMPETING CONTINUATION	$520,978
														Subtotal = $520,978

Issue Date FY: 2023 ( Subtotal = $385,000 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	5	4/27/2023	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2022 ( Subtotal = $373,449 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	4	4/19/2022	NON-COMPETING CONTINUATION	$373,449
														Subtotal = $373,449

Issue Date FY: 2021 ( Subtotal = $373,449 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	3	4/29/2021	NON-COMPETING CONTINUATION	$373,449
														Subtotal = $373,449

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	2	4/16/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $398,500 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Vision Research	000	1	4/23/2019	NEW	$398,500
														Subtotal = $398,500

Grand Total All Awards = $2,436,376

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Structural Dynamics in Rhodopsin Activation and Attenuation

Award Number: R01EY029343

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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