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Disease Pathogenesis and Modification for CaV1.1-Associated Hypokalemic Periodic

Award Number: R01AR063182
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Hypokalemic periodic paralysis (HypoPP) is a dominantly inherited disorder of skeletal muscle in which recurrent attacks of weakness are caused by intermittent failure of fiber excitability. Episodes occur in association with hypokalemia (K+ <3 mM) and are often triggered by carbohydrate ingestion, exercise, or stress. The molecular defect in HypoPP is heterogeneous, with 60% of families having missense mutations in CACNA1S encoding the L-type Ca channel CaV1.1, and 20% have missense mutations in SCN4A encoding the voltage-gated Na channel NaV1.4. Despite this scientific advance, the pathogenic basis for the transient attacks of fiber depolarization and loss of excitability is not fully established, and effective clinical interventions are lacking. The proposed studies are designed to advance our understanding of the functional defects caused by CaV1.1 HypoPP mutations and to apply this information in model simulations to gain insights on disease mechanism and thereby identify experimentally testable strategies for disease modification. All 10 HypoPP mutations in NaV1.4 and 9 of 11 in CaV1.1 occur at arginine residues in S4 segments of voltage-sensor domains (VSD). For NaV1.4 HypoPP, these R/X mutations make channels leaky because of a small anomalous “gating pore current”. By homology, a similar defect has been proposed for CaV1.1 HypoPP, but experimental confirmation has been limited. In the prior cycle of this project, we detected a CaV1.1 gating pore current in our R528H knockin mutant mouse model of HypoPP. This finding supports the notion that the anomalous gating pore current is a feature in common between NaV1.4 and CaV1.1 HypoPP mutant channels, and thereby explains how mutations of either channel can produce the same clinical phenotype. The CaV1.1-R528H mice have a robust HypoPP phenotype and are a unique resource for investigating mechanisms by which environmental triggers elicit loss of excitability and weakness. For example, we recently discovered that recovery from acidosis is a potent trigger for a transient loss of force in soleus muscle of R528H mice, which may provide the first insight on why attacks of weakness frequently occur after strenuous exercise in HypoPP patients. The availability of fully-differentiated HypoPP muscle fibers provides an excellent system to study excitation-contraction coupling, and Ca2+ release is markedly suppressed in homozygous R528H fibers. In other preliminary studies, we have achieved a 50-fold increase of CaV1.1 expression in Xenopus oocytes by co-expressing Stac3, a chaperone that promotes CaV trafficking to the membrane. This new high-expression system now makes it possible to determine whether the other CaV1.1 HypoPP mutations, especially the two atypical mutations not at R residues in S4, also support a gating pore current. The CaV1.1-R528H HypoPP mouse and the enhanced membrane expression of CaV1.1 in Xenopus oocytes will be used to address the following Specific Aims: (1) Test the hypothesis that an anomalous gating pore current is a pathomechanism in common with CaV1.1 mutations associated with HypoPP, (2) In the pH-shift model for post-exercise weakness in HypoPP, test the hypothesis that a shift in the Cl- gradient causes susceptibility to depolarization-induced loss of excitability and that maneuvers to limit Cl- accumulation reduce the severity of weakness. (3) Test whether impaired Ca2+ release is a pervasive defect in CaV1.1 R528H muscle and explore whether the defect is intrinsic to the channel mutation.


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 = $645,859 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	12/21/2023	COMPETING CONTINUATION	$645,859
														Subtotal = $645,859

Issue Date FY: 2021 ( Subtotal = $437,725 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/24/2021	NON-COMPETING CONTINUATION	$437,725
														Subtotal = $437,725

Issue Date FY: 2020 ( Subtotal = $451,263 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/17/2020	NON-COMPETING CONTINUATION	$451,263
														Subtotal = $451,263

Issue Date FY: 2019 ( Subtotal = $451,263 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	7/1/2019	NON-COMPETING CONTINUATION	$451,263
														Subtotal = $451,263

Issue Date FY: 2018 ( Subtotal = $451,263 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	7/5/2018	NON-COMPETING CONTINUATION	$451,263
2018	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	10/24/2017	COMPETING CONTINUATION	$248,579
2018	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	10/24/2017	NON-COMPETING CONTINUATION	-$248,579
														Subtotal = $451,263

Issue Date FY: 2017 ( Subtotal = $467,302 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	7/14/2017	COMPETING CONTINUATION	$467,302
2017	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/12/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $467,302

Issue Date FY: 2016 ( Subtotal = $376,758 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/17/2016	NON-COMPETING CONTINUATION	$376,758
														Subtotal = $376,758

Issue Date FY: 2015 ( Subtotal = $376,758 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	7/9/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,758
														Subtotal = $376,758

Issue Date FY: 2014 ( Subtotal = $369,222 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/19/2014	NON-COMPETING CONTINUATION	$369,222
														Subtotal = $369,222

Issue Date FY: 2013 ( Subtotal = $357,921 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/25/2013	NON-COMPETING CONTINUATION	$357,921
														Subtotal = $357,921

Issue Date FY: 2012 ( Subtotal = $387,744 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/25/2012	NEW	$387,744
														Subtotal = $387,744

Grand Total All Awards = $4,773,078

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Disease Pathogenesis and Modification for CaV1.1-Associated Hypokalemic Periodic

Award Number: R01AR063182

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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