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Dynamic changes in PIP2 binding sites and their impact on axonal targeting and function of epilepsy-associated KCNQ/Kv7 channels

Award Number: R01NS126584
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: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Dynamic changes in PIP2 binding sites and their impact on axonal targeting and function of epilepsy-associated KCNQ/Kv7 channels - PROJECT SUMMARY Neuronal Kv7/KCNQ channels are homotetramers of Kv7.2 and heterotetramers of Kv7.2 and Kv7.3 that are highly expressed in the cortex and hippocampus, key brain regions for seizure, cognition and behavior. They produce voltage-dependent outward K+ current (IM) which potently suppresses neuronal excitability. Dominant mutations in Kv7.2 and Kv7.3 cause early-onset epileptic encephalopathy (EE) with severe cognitive and behavioral deficits, stressing a critical need to understand how EE variants dysregulate Kv7 channels. Our published studies show that Kv7 channels are preferentially enriched at the axonal plasma membrane via calmodulin (CaM) binding to intracellular helices A and B of Kv7.2, which mediates their trafficking from the endoplasmic reticulum to the axonal surface. Epilepsy variants in these helices reduce their axonal enrichment and seizures in mice, underscoring the key role of axonal Kv7 channels in excitability. Importantly, membrane lipid PIP2 is an essential cofactor for opening Kv7 channels as they are potently inhibited by its membrane depletion. However, the PIP2 binding residues that regulate neuronal Kv7 channels in different states (open or closed) and complex (homomers, heteromers, or CaM-bound) are unknown. Our recent work has revealed that the PIP2-binding residues in open Kv7.2 channels are different from those in closed state and CaM-bound open channels, and that select EE mutations of these sites induce both loss and gain of PIP2 sensitivity, and reduce their axonal enrichment. Thus, the PIP2-binding landscape is dynamic and may regulate both function and trafficking of Kv7 channels. The goals of this project are to identify (i) dynamic changes in PIP2 binding residues of neuronal Kv7 channels that control their axonal enrichment and function, (ii) mechanisms by which EE variants disrupt this modulation, and (iii) compounds that reverse this dysregulation. Our central hypothesis is that dynamic and coordinated binding of PIP2 and CaM regulates activation and trafficking of axonal Kv7 channels, whereas EE mutations increase neuronal excitability by impairing formation of this complex. To test this, the present project will execute 3 specific aims using interdisciplinary approach including molecular dynamic simulations, biochemistry, imaging, and electrophysiology. Aim 1 will identify PIP2 binding residues in CaM-bound and unbound Kv7 channels and test if their PIP2 binding and sensitivity are regulated by EE mutations, Kv7 agonists and PIP2 mimetic compounds. Aim 2 will identify how PIP2 binding modulates axonal surface enrichment of CaM-bound and unbound Kv7 channels by examining their exocytosis, endocytosis, and plasma membrane retention. Aim 3 will test if loss- and gain-of PIP2 modulations of axonal Kv7 channels lead to neuronal hyperexcitability in culture and conditional knock-in mice. In contrast to a well- established role of PIP2 in gating modulation of Kv7 channels, this project will provide novel concepts that their PIP2 binding sites change dynamically and modulate both function and trafficking of axonal Kv7 channels to impact IM and neuronal excitability, and reveal novel pathogenic mechanisms of EE variants in Kv7.2 and Kv7.3.


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 = $361,493 )
2026	2026	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/25/2026	NON-COMPETING CONTINUATION	$361,493
														Subtotal = $361,493

Issue Date FY: 2025 ( Subtotal = $365,984 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/1/2025	NON-COMPETING CONTINUATION	$365,984
														Subtotal = $365,984

Issue Date FY: 2024 ( Subtotal = $362,331 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/27/2024	NON-COMPETING CONTINUATION	$362,331
														Subtotal = $362,331

Issue Date FY: 2023 ( Subtotal = $380,470 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/13/2023	NEW	$326,113
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/29/2023	NEW	$54,357
														Subtotal = $380,470

Grand Total All Awards = $1,470,278

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Dynamic changes in PIP2 binding sites and their impact on axonal targeting and function of epilepsy-associated KCNQ/Kv7 channels

Award Number: R01NS126584

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: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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