Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current

Gillet, Ludovic; Rougier, Jean-Sébastien; Shy, Diana Amy; Sonntag, Stephan; Mougenot, Nathalie; Essers, Maria Cristina; Shmerling, Doron; Balse, Elise; Hatem, Stéphane N; Abriel, Hugues (2015). Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current. Heart rhythm, 12(1), pp. 181-192. Elsevier 10.1016/j.hrthm.2014.09.057

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BACKGROUND Membrane-associated guanylate kinase (MAGUK) proteins are important determinants of ion channel organization in the plasma membrane. In the heart, the MAGUK protein SAP97, encoded by the DLG1 gene, interacts with several ion channels via their PDZ domain-binding motif and regulates their function and localization. OBJECTIVE The purpose of this study was to assess in vivo the role of SAP97 in the heart by generating a genetically modified mouse model in which SAP97 is suppressed exclusively in cardiomyocytes. METHODS SAP97(fl/fl) mice were generated by inserting loxP sequences flanking exons 1-3 of the SAP97 gene. SAP97(fl/fl) mice were crossed with αMHC-Cre mice to generate αMHC-Cre/SAP97(fl/fl) mice, thus resulting in a cardiomyocyte-specific deletion of SAP97. Quantitative reverse transcriptase-polymerase chain reaction, western blots, and immunostaining were performed to measure mRNA and protein expression levels, and ion channel localization. The patch-clamp technique was used to record ion currents and action potentials. Echocardiography and surface ECGs were performed on anesthetized mice. RESULTS Action potential duration was greatly prolonged in αMHC-Cre/SAP97(fl/fl) cardiomyocytes compared to SAP97(fl/fl) controls, but maximal upstroke velocity was unchanged. This was consistent with the decreases observed in IK1, Ito, and IKur potassium currents and the absence of effect on the sodium current INa. Surface ECG revealed an increased corrected QT interval in αMHC-Cre/SAP97(fl/fl) mice. CONCLUSION These data suggest that ablation of SAP97 in the mouse heart mainly alters potassium channel function. Based on the important role of SAP97 in regulating the QT interval, DLG1 may be a susceptibility gene to be investigated in patients with congenital long QT syndrome.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Gillet, Ludovic; Rougier, Jean-Sébastien; Shy, Diana Amy; Essers, Maria Cristina and Abriel, Hugues

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1547-5271

Publisher:

Elsevier

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

13 Mar 2015 10:33

Last Modified:

02 Nov 2015 11:01

Publisher DOI:

10.1016/j.hrthm.2014.09.057

PubMed ID:

25447080

Uncontrolled Keywords:

Action potential, Potassium channel, SAP97, Sodium channel, Tissue-specific knockout

BORIS DOI:

10.7892/boris.64455

URI:

https://boris.unibe.ch/id/eprint/64455

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