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Alternative Mechanisms of Signaling Via Trimeric G Proteins

Award Number: R01NS117101
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: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Alternative Mechanisms of Signaling Via Trimeric G Proteins - SIGNIFICANCE: Our long-term goal is to discover novel regulatory components of a core mechanism of cellular communication, i.e., signaling via heterotrimeric G proteins (henceforth trimeric G proteins), and to characterize the molecular mechanisms that underlie their involvement in human disease. Our emphasis is on cytoplasmic factors that regulate G protein signaling, which have been (and remain) understudied compared to G protein-coupled receptors (GPCRs), the main activating inputs for trimeric G proteins. During the last grant cycle, we made significant advances in this area by achieving all the originally proposed goals, thereby establishing a new paradigm of G protein regulation. We demonstrated the existence of a family of cytoplasmic activators of G proteins, dissected the structural basis for their molecular activity, and established the consequences of their dysregulation in specific cellular processes and human diseases. The specific goal of this renewal application is to characterize the prototype member of a potential new class of G protein regulators that has been linked to chronic pain and epilepsy. The achievement of our goals would provide deep mechanistic insights into a new paradigm of GPCR-G protein regulation that fine tunes inhibitory neuromodulation, and establish a new framework to devise therapeutic strategies for neurological disorders like chronic pain and epilepsy. BACKGROUND: In the course of a screen of proteins that bind to Gαi subunits of Gα-Gβγ timeric complexes, we identified a protein that regulates G proteins via a unique and novel mechanism. We have coined the term “paradoxical G protein regulator” (PGR) to convey that it upregulates the modulation of some G protein effectors while simultaneously downregulating the modulation of other G protein effectors. Loss of this “PGR” is known to alter GPCR signaling in neurons of the peripheral nervous system and causes chronic pain. It has also been linked to epilepsy. Despite its clear biomedical importance, the molecular mechanism by which this G protein regulator operates, and how it modulates neurotransmission in the brain are completely unknown. SYNOPSIS OF AIMS: Based on compelling preliminary data, we propose that the PGR modulates both Gαi- and Gβγ-dependent signaling without directly affecting the G protein enzymatic activity (i.e., nucleotide binding and/or hydrolysis), and that this novel mechanism fine tunes GPCR signaling in brain neurons to influence seizure susceptibility. In Aim#1 we will dissect how the PGR regulates G proteins at the molecular level by characterizing how it engages physically Gαi and the consequences of this physical engagement on G protein signaling to different effectors. In Aim#2 we will characterize how it regulates GPCR signaling and neurotransmission at the cellular level by using primary cultures of neurons and brain slices from wild-type and KO mice. In Aim#3 we will determine the PGR's role at the physiological level by establishing how it impacts seizure susceptibility using genetically modified mouse models.


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 = $457,778 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	4/8/2024	NON-COMPETING CONTINUATION	$33,034
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/20/2024	NON-COMPETING CONTINUATION	$424,744
														Subtotal = $457,778

Issue Date FY: 2023 ( Subtotal = $471,937 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/22/2023	NON-COMPETING CONTINUATION	$471,937
														Subtotal = $471,937

Issue Date FY: 2022 ( Subtotal = $808,743 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/15/2022	NON-COMPETING CONTINUATION	$430,865
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	3/23/2022	NON-COMPETING CONTINUATION	$47,878
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	5/27/2022	SUPPLEMENT FOR EXPANSION	$330,000
														Subtotal = $808,743

Issue Date FY: 2021 ( Subtotal = $486,272 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/18/2021	NON-COMPETING CONTINUATION	$485,549
2021	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	6/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$723
														Subtotal = $486,272

Issue Date FY: 2020 ( Subtotal = $515,412 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$515,412
														Subtotal = $515,412

Grand Total All Awards = $2,740,142

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Alternative Mechanisms of Signaling Via Trimeric G Proteins

Award Number: R01NS117101

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: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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