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Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons

Award Number: R01NS094461
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Multi-protein complexes have emerged as a mechanism for spatiotemporal specificity and efficiency in the function and regulation of myriad cellular signals. In particular, many ion channels are clustered either with the receptors that modulate them, or with other ion channels whose activities are linked. Often, the clustering is mediated by scaffolding proteins, such as the AKAP79/150 protein that is a focus of this grant. We focus on three different channels critical to nervous function. One is the "M-type" (KCNQ, Kv7) K+ channel that plays fundamental roles in the regulation of excitability in nerve and muscle. It is thought to associate with Gq/11- coupled receptors, protein kinases, calcineurin (CaN), calmodulin (CaM) and phosphoinositides via AKAP79/150. Another channel of focus is TRPV1, a nociceptive channel in sensory neurons that is also thought to be regulated by signaling proteins recruited by AKAP79/150. The third are L-type Ca2+ (CaV1.2) channels that are critical to synaptic plasticity, gene regulation and neuronal firing. We will probe complexes containing AKAP79/150 and these three channels using "super-resolution" STORM imaging of primary sensory neurons and heterologously-expressed tissue-culture cells, in which individual complexes can be visualized at 10-20 nm resolution with visible light, breaking the diffraction barrier of physics. We hypothesize that AKAP79/150 brings several of these channels together to enable functional coupling, which we will examine by patch-clamp electrophysiology of the neurons. Förster resonance energy transfer (FRET) will also be performed under total internal reflection fluorescence (TIRF) or confocal microscopy, further testing for complexes containing KCNQ, TRPV1 and CaV1.2 channels. Since all three of these channels bind to AKAP79/150, we hypothesize that they co-assemble into complexes in neurons, together with certain G protein-coupled receptors. Furthermore, we hypothesize these complexes to not be static, but rather to be dynamically regulated by other cellular signals, which we will examine using rapid activation of kinases or phosphatases. Several types of mouse colonies of genetically altered AKAP150 knock-out or knock-in mice will be utilized. This project breaks new ground into the physiology of signaling in neurons, using several cutting-edge, high- powered approaches that have just recently been developed.


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 = -$10,846 )
2025	2019	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	10/1/2024	SUPPLEMENT FOR EXPANSION	-$10,846
														Subtotal = -$10,846

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $703,969 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/2/2019	SUPPLEMENT FOR EXPANSION	$373,591
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/12/2019	NON-COMPETING CONTINUATION	$330,378
														Subtotal = $703,969

Issue Date FY: 2018 ( Subtotal = $330,378 )
2018	2018	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/9/2018	NON-COMPETING CONTINUATION	$330,378
														Subtotal = $330,378

Issue Date FY: 2017 ( Subtotal = $330,378 )
2017	2017	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/11/2017	NON-COMPETING CONTINUATION	$330,378
														Subtotal = $330,378

Issue Date FY: 2016 ( Subtotal = $350,378 )
2016	2016	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/3/2016	SUPPLEMENT FOR EXPANSION	$20,000
2016	2016	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/11/2016	NON-COMPETING CONTINUATION	$330,378
														Subtotal = $350,378

Issue Date FY: 2015 ( Subtotal = $330,378 )
2015	2015	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78229	BEXAR	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/24/2015	NEW	$330,378
														Subtotal = $330,378

Grand Total All Awards = $2,034,635

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Clustering of individual and diverse ion channels together into complexes, and their functional coupling, mediated by A-kinase anchoring protein 79/150 in neurons

Award Number: R01NS094461

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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