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Structure and Function of Pannexins: Activation Mechanism

Award Number: R01GM114379
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Structure and Function of Pannexins: Activation Mechanism - ABSTRACT Pannexins comprise a unique family of heptameric large-pore channels that are emerging as novel targets for treating common, yet hard to cure diseases such as hypertension and chronic pain. Previous studies indicate that Panx1 is activated through stimulation of structurally unrelated receptors such as G protein- coupled receptors, ligand-gated ion channels, and tumor necrosis factor receptors. However, it remains un- clear what cellular mechanism(s) actually open and close the Panx1 channel downstream of such seemingly unrelated stimuli. Furthermore, Panx2 and 3 are severely understudied and essentially nothing is known about the activation mechanisms of these subtypes. The long-term goal is to elucidate the mechanisms underlying pannexin gating, regulation, and physiological signaling pathways. The specific objectives for this proposal are to identify the physiological pannexin activators and elucidate the subtype-specific activation mechanisms. The central hypothesis is that both Panx1 and 2 are directly activated by naturally occurring signaling mole- cules in living cells and that Panx1 specifically requires posttranslational modifications to be primed for its activation. The rationale for the proposed research is that once the direct activation-stimuli and the subtype- specific mechanisms are identified, it will enable us to fill the critical gap in the pannexin-dependent signaling pathway by connecting the upstream cell-stimulation and the downstream ATP-permeable membrane pore formation. To attain the overall objectives, the following three specific aims will be performed:1) Identify the direct pannexin activators for living cells; 2) Elucidate the role of the N-terminal domain (NTD) in pannexin activation; and 3) Uncover the subtype-specific structural features of pannexins. These research aims will be executed by using a combination of a cell-based pannexin activity assay, electrophysiology, functional recon- stitution, and cryo-EM. The research proposed in this application is innovative because it introduces a novel concept that pannexins—including the understudied Panx2—are directly activated by signaling molecules produced downstream of various stimuli in living cells. It is also innovative because it will provide important insights into the structure of the open channel and why Panx2 and 3 behave differently from Panx1. The proposed research is significant because it will provide concrete molecular mechanisms for the missing link in the pannexin signaling function. The proposed research is also expected to provide a strong structural foundation for subtype specific mechanisms of pannexin channels. These results are expected to have pro- found positive impact not only because they provide detailed basic mechanisms, but also because they will open a new door for screening/designing pannexin-specific inhibitors—much-needed molecular tools that have great potentials to serve as novel therapeutics for a variety of currently uncurable diseases.


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 = $293,370 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	9	2/21/2025	NON-COMPETING CONTINUATION	$293,370
														Subtotal = $293,370

Issue Date FY: 2024 ( Subtotal = $444,728 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	8	2/16/2024	NON-COMPETING CONTINUATION	$294,582
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	8	7/25/2024	NON-COMPETING CONTINUATION	$32,732
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	8	8/7/2024	SUPPLEMENT FOR EXPANSION	$117,414
														Subtotal = $444,728

Issue Date FY: 2023 ( Subtotal = $328,620 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	7	2/10/2023	NON-COMPETING CONTINUATION	$328,620
														Subtotal = $328,620

Issue Date FY: 2022 ( Subtotal = $328,685 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	6	4/11/2022	COMPETING CONTINUATION	$328,685
														Subtotal = $328,685

Issue Date FY: 2021 ( Subtotal = -$9,253 )
2021	2019	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	5	2/6/2021	NON-COMPETING CONTINUATION	-$9,253
														Subtotal = -$9,253

Issue Date FY: 2019 ( Subtotal = $381,723 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	002	5	8/22/2019	NON-COMPETING CONTINUATION	$317,800
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	7/10/2019	SUPPLEMENT FOR EXPANSION	$14,444
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	4	8/21/2019	SUPPLEMENT FOR EXPANSION	$49,479
														Subtotal = $381,723

Issue Date FY: 2018 ( Subtotal = $302,905 )
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	8/30/2018	NON-COMPETING CONTINUATION	$302,905
														Subtotal = $302,905

Issue Date FY: 2017 ( Subtotal = $345,603 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	3	8/29/2017	NON-COMPETING CONTINUATION	$302,467
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	3	9/5/2017	SUPPLEMENT FOR EXPANSION	$43,136
														Subtotal = $345,603

Issue Date FY: 2016 ( Subtotal = $290,683 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	2	8/12/2016	NON-COMPETING CONTINUATION	$302,042
2016	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	11/20/2015	NEW	-$11,359
														Subtotal = $290,683

Issue Date FY: 2015 ( Subtotal = $312,989 )
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	8/28/2015	NEW	$312,989
														Subtotal = $312,989

Grand Total All Awards = $3,020,053

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Structure and Function of Pannexins: Activation Mechanism

Award Number: R01GM114379

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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