What question did this study set out to answer?

To determine the role of LITAF in modulating cardiac excitation and regulating cardiac L-type calcium channels.

September 1, 2019Circulation Genomic and Precision MedicineOpen Access

LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase

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Why the study?

A genetic variant upstream of LITAF identified in QT interval genome-wide association studies prompted evaluation of its role in modulating cardiac excitation.

Population

Zebrafish hearts, adult and 3-week-old rabbit cardiomyocytes, and tsA201 cells

Comparison

LITAF knockdown or overexpression vs control conditions

Design

Preclinical experimental study

Authors

KMKarni S. MoshalUniversity of Nevada, Reno KRKarim RoderBrown University AKAnatoli Y. KabakovBrown University

Discussion

Member takes

Implication

Should not yet change practice; leaves open whether this pathway can be targeted in human calcium-channel disorders.

Key Points

To determine the role of LITAF in modulating cardiac excitation and regulating cardiac L-type calcium channels.
Assessed Ca2+ transients using optical mapping in zebrafish hearts and live-cell confocal calcium imaging in adult rabbit cardiomyocytes.
Measured L-type calcium channel current (ICa,L) and Cav1.2 channel abundance via whole-cell patch-clamp recording, cell-surface biotinylation, and Western blotting.
Evaluated LITAF interactions and ubiquitination dynamics in tsA201 cells and cardiomyocytes using coimmunoprecipitation, in situ proximity ligation assays, and computer simulations.
LITAF knockdown in zebrafish markedly elevated calcium transients, whereas LITAF overexpression in rabbit cardiomyocytes decreased ICa,L, Cavα1c protein abundance, and calcium transients.
LITAF promoted the downregulation of total and surface Cavα1c in tsA201 cells by enhancing NEDD4-1-mediated ubiquitination and subsequent lysosomal degradation.
Knockdown of NEDD4-1 abolished the inhibitory effects of LITAF on ICa,L and Cavα1c levels, while computational modeling confirmed that LITAF-driven ICa,L reduction shortened action potential duration.

Structured PICO

Population

Zebrafish hearts, adult and 3-week-old rabbit cardiomyocytes, and tsA201 cells

Intervention

LITAF knockdown or overexpression

Comparator

Control (implied)

Outcome

Calcium transients, L-type calcium channel (LTCC) current (ICa,L), and Cavα1c abundance/ubiquitinationsurrogate

LITAF regulates cardiac excitation by promoting NEDD4-1-mediated ubiquitination and degradation of L-type calcium channels.

Cite This Study

Moshal et al. (2019) studied this question.

synapsesocial.com/papers/6a7fb1cd044998269cd77179 https://doi.org/10.1161/circgen.119.002641

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LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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