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Channelopathy of KCa2.3 and Zimmermann-Laband syndrome

Award Number: R15NS130420
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Channelopathy of KCa2.3 and Zimmermann-Laband syndrome - ABSTRACT Zimmermann-Laband syndrome 3 (ZLS3 [MIM: 618658]) is a rare genetic developmental disorder characterized by gingival enlargement, developmental delay, intellectual disability, together with abnormal fingers, fingernails, nose, and ears. Small-conductance Ca2+-activated K+ subtype 3 (KCa2.3) channels are activated exclusively by intracellular Ca2+. There are seven human genetic mutations of KCa2.3 linked to ZLS31- 3 and one mutation associated with idiopathic noncirrhotic portal hypertension (INCPH)4. No treatment for ZLS3 exists. We recently reported that the ZLS3-related mutations in KCa2.3 increase the Ca2+ sensitivity of the channels more than the INCPH-related mutation5. We hypothesize that disease-related KCa2.3 mutations cause abnormally elevated Ca2+ sensitivity of the channel, a theory that will be tested in Aim 1. To correct the abnormally elevated Ca2+ sensitivity, we will need to understand the mechanisms of how Ca2+ sensitivity is increased by the KCa2.3 mutations. These mutations can be separated into three clusters in the channel protein1-3. The first cluster are localized at a region that we reported essential for channel gating6. The second cluster are reported to interact with casein kinase 2 (CK2)7. CK2 phosphorylates calmodulin (CaM) constitutively associated with KCa2.3 channels and thus negatively modulates Ca2+ sensitivity8, 9. The last mutation, A287S, is in the transmembrane S1 domain. We postulated that the first cluster of five mutations in KCa2.3 may enlarge the channel gate and make the channel easier to open as the mechanism for their elevated sensitivity to Ca2+. The second cluster of mutant KCa2.3 channels may not affect the channel gate directly but rather CK2 phosphorylation. The mechanisms for the elevated Ca2+ sensitivity of ZLS3-related mutant channels will be elucidated in Aim 2. As the KCa2.3 mutations elevate the Ca2+ sensitivity through differential mechanisms, the seven ZLS3-related KCa2.3 mutations may also lead to different sensitivities to channel inhibitors. In our preliminary studies, the effect of AP14145, a negative gating modulator, on the mutant channels was less prominent than on the wild-type channels5, highlighting the need for compounds that inhibit mutant channels. We will explore FDA-approved drugs and compounds in clinical trials that have been reported to inhibit KCa2.3 channels as candidates for off- label or compassionate use in Aim 3. PUBLIC HEALTHE RELEVANCE: There are seven human genetic mutations of KCa2.3 linked to ZLS31-3 and one mutation associated with idiopathic noncirrhotic portal hypertension (INCPH)4. We will explore FDA- approved drugs and compounds in clinical trials that inhibit KCa2.3 channels as candidates for off-label or compassionate use.


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 = $0 )
2026	2024	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/29/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $434,024 )
2024	2024	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/12/2024	NEW	$434,024
														Subtotal = $434,024

Grand Total All Awards = $434,024

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Channelopathy of KCa2.3 and Zimmermann-Laband syndrome

Award Number: R15NS130420

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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