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Molecular Dissection of Active Zone Functions in Neurotransmitter Release

Award Number: R01NS083898
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: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Molecular Dissection of Active Zone Functions in Neurotransmitter Release - Summary Within a nerve terminal, neurotransmitter-filled vesicles fuse at the active zone. The active zone consists of protein scaffolds that are anchored to the plasma membrane and form sites for vesicle fusion, and active zone proteins mediate both the release of synaptic and neuromodulatory transmitters. Interactions between active zone proteins and voltage-gated Ca2+ channels (CaVs) have long been of central interest. Ca2+ influx through channels of the CaV2 family triggers secretion, and CaV2 positioning determines the sub-millisecond timing, magnitude and plasticity of release. In previous work, we distinguished between two competing models of CaV2s. In the “assembly model”, CaV2s are structural scaffolds with functions in active zone assembly and vesicle docking. In the “anchored model”, active zone proteins recruit CaV2s to anchor them to release sites, and presynaptic assembly is CaV2-independent. We found that active zone assembly and vesicle docking are unaffected by genetic ablation of CaV2s. This argues strongly against the assembly model. The alternate anchored model remains difficult to establish. It is uncertain how CaV2s are targeted to active zones and whether this model applies broadly to synaptic and neuromodulatory transmission. One line of work has found that disrupting binding between CaV2 channels and active zone proteins results in impaired CaV2 recruitment. However, no specific CaV2 binding activity is required, and it remains unknown which CaV2 sequences suffice to mediate CaV2 active zone delivery. We hypothesize that the CaV2 C-terminus contains multiple interaction motifs that together provide a module for CaV delivery to release sites in most synaptic and neuromodulatory transmitter systems. We build on two lines of preliminary data. First, we find that multiple sequence elements in the CaV2 C-terminus together mediate presynaptic delivery, and that they can serve to target non-active zone CaVs to release sites. Second, our experiments suggest that release of two volume transmitters, serotonin and acetylcholine, fully depends on CaV2s. In aim 1, we define CaV2 sequences that mediate CaV active zone targeting at hippocampal synapses. In aim 2, we determine the CaV2-dependence of neuromodulatory transmitter release in the brain, focusing on serotonin, acetylcholine and norepinephrine. Our work will establish mechanisms of CaV2 targeting to the active zone and will determine whether these mechanisms can fundamentally operate in both synaptic and neuromodulatory transmission through assessing their CaV2 dependence. Altogether, the proposed experiments will likely lead to broad support for the anchored model across transmitter systems. The understanding of CaV2s that we develop in this line of work is important for determining how neurotransmission operates and how it breaks down in disease.


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 = $528,957 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	12	7/15/2025	NON-COMPETING CONTINUATION	$528,957
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	2/26/2025	COMPETING CONTINUATION	$37,633
2025	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/26/2025	NON-COMPETING CONTINUATION	-$37,633
														Subtotal = $528,957

Issue Date FY: 2024 ( Subtotal = $528,957 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	4/1/2024	COMPETING CONTINUATION	$528,957
														Subtotal = $528,957

Issue Date FY: 2023 ( Subtotal = $500,407 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	5/3/2023	NON-COMPETING CONTINUATION	$500,407
														Subtotal = $500,407

Issue Date FY: 2022 ( Subtotal = $500,407 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/25/2022	NON-COMPETING CONTINUATION	$500,407
														Subtotal = $500,407

Issue Date FY: 2021 ( Subtotal = $500,407 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/14/2021	NON-COMPETING CONTINUATION	$500,407
														Subtotal = $500,407

Issue Date FY: 2020 ( Subtotal = $500,407 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	4/15/2020	NON-COMPETING CONTINUATION	$500,407
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/27/2020	COMPETING CONTINUATION	$29,611
2020	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/27/2020	NON-COMPETING CONTINUATION	-$29,611
														Subtotal = $500,407

Issue Date FY: 2019 ( Subtotal = $500,407 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	7/26/2019	COMPETING CONTINUATION	$500,407
2019	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/24/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $500,407

Issue Date FY: 2018 ( Subtotal = $370,781 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/11/2018	NON-COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2017 ( Subtotal = $370,781 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/31/2017	NON-COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2016 ( Subtotal = $370,781 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/18/2016	NON-COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2015 ( Subtotal = $370,781 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/8/2015	NON-COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2014 ( Subtotal = $370,781 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/19/2014	NEW	$370,781
														Subtotal = $370,781

Grand Total All Awards = $5,413,854

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Molecular Dissection of Active Zone Functions in Neurotransmitter Release

Award Number: R01NS083898

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: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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