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Synaptotagmin C2B Domain as a Ca2+ Sensing Module

Award Number: R01MH061876
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2002
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Synaptotagmin C2B Domain as a Ca2+ Sensing Module - Project Summary/Abstract In this competitive renewal, we continue our studies of synaptotagmin (syt) isoforms that regulate the release of neurotransmitters and hormones. The founding member of this gene family, syt1, was discovered in 1981 and has been shown to function as the major Ca2+ sensor for synchronous synaptic vesicle (SV) exocytosis in neurons. Surprisingly, the most fundamental property of syt1—it's ability to bind and become activated by Ca2+—remains one of its least understood properties. Syt1 senses Ca2+ via tandem C2 domains, C2A and C2B, and five acidic Ca2+ binding residues have been proposed to coordinate 2-3 Ca2+ ions per domain. However, substitution of these residues in C2A has led to considerable confusion, with conflicting results as to whether these mutations are loss- or gain-of-function or have no effect at all; C2B has been studied in even less detail. In Aim 1 we propose quantitative experiments to compare the roles of each of these putative ligands in binding Ca2+, via isothermal titration calorimetry, and in release, via Ca2+ dose-response measurements of exocytosis using iGluSnFR. In Aim 2, we address the function of syt9, which is perhaps the most misunderstood isoform. Syt9 is in the same clade as syt1 and was proposed to trigger SV release in striatal neurons. Our preliminary data revealed that this is not the case; rather, syt9 is mainly targeted to dense core vesicles in striatal neurons where it regulates the release of substance P, to indirectly control spontaneous SV fusion rates. We will delve into this model by conducting syt9 structure-function studies using both reconstituted fusion assays and syt9 KO neurons, and by conducting pharmacological experiments. We will also expand this work to striatal slices, where substance P has been shown to strongly modulate dopamine release. Importantly, dopaminergic transmission in the striatum plays a key role in addiction and schizophrenia. So, we will conduct experiments to determine whether syt9-regulated substance P release modulates dopamine release in this brain region. Finally, in Aim 3 we return to syt1, to compare its role in activity- dependent SV docking with another isoform, syt7. SV docking dynamics have recently emerged as a key step in numerous aspects of release and short-term plasticity. Using our newly acquired zap-and-freeze instrument, combined with cryo-EM tomography, we will test the idea that syt1 mediates activity-dependent SV docking on short time scales to impact synchronous release, whereas syt7 mediates activity-dependent SV docking on longer time scales to impact asynchronous release, paired-pulse facilitation, and synaptic depression. Collectively, the three Aims proposed here will significantly advance our understanding of the functions of three distinct syt isoforms. In short, we will: 1) address the most elementary questions concerning how the founding member, syt1, senses Ca2+, 2) conduct a rigorous analysis of syt9 function in striatal neurons and, 3) use state-of-the-art approaches to time-resolve the roles of syt1 and syt7 in the newly discovered phenomenon of activity-dependent docking, to—in turn—control elementary aspects of release and plasticity.


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 = $368,770 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	23	3/24/2026	NON-COMPETING CONTINUATION	$368,770
														Subtotal = $368,770

Issue Date FY: 2025 ( Subtotal = $368,770 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	22	3/11/2025	NON-COMPETING CONTINUATION	$313,455
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	002	22	9/18/2025	NON-COMPETING CONTINUATION	$55,315
2025	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	19	1/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,770

Issue Date FY: 2024 ( Subtotal = $368,770 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	21	8/15/2024	NON-COMPETING CONTINUATION	$36,877
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	21	3/6/2024	NON-COMPETING CONTINUATION	$331,893
														Subtotal = $368,770

Issue Date FY: 2023 ( Subtotal = $368,770 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	20	6/16/2023	COMPETING CONTINUATION	$368,770
2023	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	19	6/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,770

Issue Date FY: 2022 ( Subtotal = $376,140 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	19	3/23/2022	NON-COMPETING CONTINUATION	$376,140
														Subtotal = $376,140

Issue Date FY: 2021 ( Subtotal = $376,140 )
2021	2021	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	18	3/5/2021	NON-COMPETING CONTINUATION	$376,140
														Subtotal = $376,140

Issue Date FY: 2020 ( Subtotal = $376,140 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	17	3/19/2020	NON-COMPETING CONTINUATION	$376,140
														Subtotal = $376,140

Issue Date FY: 2019 ( Subtotal = $376,140 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	002	16	4/12/2019	NON-COMPETING CONTINUATION	$376,140
2019	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	15	10/24/2018	COMPETING CONTINUATION	$145,087
2019	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	14	10/24/2018	NON-COMPETING CONTINUATION	-$145,087
														Subtotal = $376,140

Issue Date FY: 2018 ( Subtotal = $376,140 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	15	5/31/2018	COMPETING CONTINUATION	$376,140
2018	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	14	5/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,140

Issue Date FY: 2017 ( Subtotal = $360,090 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	14	7/25/2017	NON-COMPETING CONTINUATION	$36,009
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	14	3/9/2017	NON-COMPETING CONTINUATION	$324,081
														Subtotal = $360,090

Issue Date FY: 2016 ( Subtotal = $360,090 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	13	3/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$360,090
														Subtotal = $360,090

Issue Date FY: 2015 ( Subtotal = $360,090 )
2015	2015	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	12	3/4/2015	NON-COMPETING CONTINUATION	$360,090
														Subtotal = $360,090

Issue Date FY: 2014 ( Subtotal = $360,090 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	11	3/7/2014	NON-COMPETING CONTINUATION	$360,090
														Subtotal = $360,090

Issue Date FY: 2013 ( Subtotal = $360,090 )
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	10	3/27/2013	COMPETING CONTINUATION	$360,090
2013	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	9	3/22/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $360,090

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	9	7/4/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $287,158 )
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	9	6/17/2011	NON-COMPETING CONTINUATION	$287,158
														Subtotal = $287,158

Issue Date FY: 2010 ( Subtotal = $290,280 )
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	8	6/4/2010	NON-COMPETING CONTINUATION	$290,280
														Subtotal = $290,280

Issue Date FY: 2009 ( Subtotal = $340,495 )
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	001	7	9/29/2009	SUPPLEMENT FOR EXPANSION	$50,000
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	7	6/25/2009	NON-COMPETING CONTINUATION	$290,495
														Subtotal = $340,495

Issue Date FY: 2008 ( Subtotal = $290,704 )
2008	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	6	5/27/2008	NON-COMPETING CONTINUATION	$290,704
														Subtotal = $290,704

Issue Date FY: 2007 ( Subtotal = $290,907 )
2007	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Mental Health Research Grants	000	5	8/28/2007	COMPETING CONTINUATION	$290,907
														Subtotal = $290,907

Grand Total All Awards = $7,710,857

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Synaptotagmin C2B Domain as a Ca2+ Sensing Module

Award Number: R01MH061876

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2002

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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