Key result
Two novel ankyrin-B isoforms, AnkB-188 and AnkB-212, were identified in mammalian hearts and shown to have distinct subcellular distributions and functions regulating specific protein interactions.
Alternative splicing of the ANK2 gene produces two functionally distinct ankyrin-B isoforms that regulate specific protein interactions and excitation-contraction coupling in the heart.
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Extends ANK2 splicing biology in mammalian hearts; leaves open relevance to human arrhythmias or therapies.
AIMS: Excitation-contraction coupling in cardiomyocytes requires the proper targeting and retention of membrane proteins to unique domains by adaptor proteins like ankyrin-B. While ankyrin-B has been shown to interact with a variety of membrane and structural proteins located at different subcellular domains in cardiomyocytes, what regulates the specificity of ankyrin-B for particular interacting proteins remains elusive. METHODS AND RESULTS: Here, we report the identification of two novel ankyrin-B isoforms AnkB-188 and AnkB-212 in human, rat, and mouse hearts. Novel cDNAs for both isoforms were isolated by long-range PCR of reverse-transcribed mRNA isolated from human ventricular tissue. The isoforms can be discriminated based on their function and subcellular distribution in cardiomyocytes. Heterologous overexpression of AnkB-188 increases sodium-calcium exchanger (NCX) membrane expression and current, while selective knockdown of AnkB-188 in cardiomyocytes reduces NCX expression and localization in addition to causing irregular contraction rhythms. Using an isoform-specific antibody, we demonstrate that the expression of AnkB-212 is restricted to striated muscles and is localized to the M-line of cardiomyocytes by interacting with obscurin. Selective knockdown of AnkB-212 significantly attenuates the expression of endogenous ankyrin-B at the M-line but does not disrupt NCX expression at transverse tubules in cardiomyocytes. CONCLUSION: The identification and characterization of two functionally distinct ankyrin-B isoforms in heart provide compelling evidence that alternative splicing of the ANK2 gene regulates the fidelity of ankyrin-B interactions with proteins.
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Wu et al. (2015) studied this question. AnkB-188 and AnkB-212 overexpression or knockdown was evaluated on Function and subcellular distribution of ankyrin-B isoforms. Two novel ankyrin-B isoforms, AnkB-188 and AnkB-212, were identified in mammalian hearts and shown to have distinct subcellular distributions and functions regulating specific protein interactions.
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