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Regulation of exocytosis by direct Gbg blockade of fusion

Award Number: R01NS111749
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: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Regulation of exocytosis by direct Gbg blockade of fusion - Summary Inhibition of secretion by Gi/o-coupled GPCRs is an important control mechanism used by many hormones and neuromodulators. It is well documented that activation of Gi/o-coupled GPCRs in secretory cells releases G subunits that inhibit Ca2+ entry through voltage-dependent Ca2+ channels (VDCCs), leading to reduced hormone release. However, a direct interaction between G and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins also inhibits transmitter hormone release in many systems. This mechanism is not only more acute and direct in controlling evoked release but also has the ability to modify spontaneous release. However, the mechanistic details of this SNARE-mediated modulation remain understudied, with many open questions. For example, which GPCRs work through this mechanism? We have also found that G inhibition of Ca2+ entry synergizes with G inhibition of SNARE-mediated exocytosis. We will address the mechanism of this synergism as well as it’s implications in physiology. Adding another layer of complexity is the diversity of G and G isoforms and the control of specificity of Gs. Using proteomic assays, we have found that specific G subunits (i.e. G12) bind to SNARE even without GPCR agonists whereas adding agonists enhances G12 binding but also brings new Gs (e.g. G23) to SNAREs. These data suggest that unique G subunits can differentially act on SNARE to achieve different degrees of modulation via GPCRs or even without GPCR activation. Therefore, we propose that SNARE-mediated G modulation of hormone release exerts its functional diversity by different combination of G subunits and different degree of SNARE binding. This leads us to focus on three specific aims that test (1) which GPCRs work through modulation of Ca2+ entry and which work through binding SNARE (2) what is the mechanism of synergism between the two G-mediated mechanisms and (3) what is the role of particular G and  subunits in GPCR regulation of hormone release. Given the huge diversity of GPCRs in CNS, given G’s close ties to modulation of exocytosis, and given their relevance to many hormonal and neurological disorders, this project will illuminate a more versatile modulation of secretion by different Gs, bridge the knowledge gap between tonic and phasic modulation of release via GPCRs in secretion, and unravel molecular mechanisms underpinning various hormonal and neurological disorders.


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: 2024 ( Subtotal = $0 )
2024	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $402,313 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/25/2023	NON-COMPETING CONTINUATION	$362,082
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/2/2023	NON-COMPETING CONTINUATION	$40,231
														Subtotal = $402,313

Issue Date FY: 2022 ( Subtotal = $404,951 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/20/2022	NON-COMPETING CONTINUATION	$40,495
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/20/2021	NON-COMPETING CONTINUATION	$364,456
														Subtotal = $404,951

Issue Date FY: 2021 ( Subtotal = $407,589 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/8/2021	NON-COMPETING CONTINUATION	$407,589
														Subtotal = $407,589

Issue Date FY: 2020 ( Subtotal = $407,589 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/13/2020	NON-COMPETING CONTINUATION	$40,759
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/14/2020	NON-COMPETING CONTINUATION	$366,830
														Subtotal = $407,589

Issue Date FY: 2019 ( Subtotal = $421,839 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/26/2019	NEW	$421,839
														Subtotal = $421,839

Grand Total All Awards = $2,044,281

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Regulation of exocytosis by direct Gbg blockade of fusion

Award Number: R01NS111749

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: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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