SLMAP3 isoform modulates cardiac gene expression and function.

Jana Mlynarova,Jennifer L Major,Mayra Trentin-Sonoda,Maysoon Salih,Fernanda Gaisler Da Silva,Balwant S Tuana,Marcela S Carneiro-Ramos,Peter H Backx

doi:10.1371/journal.pone.0214669

Jana Mlynarova, Jennifer L Major + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0214669

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Journal: PloS one	Publication Date: Apr 1, 2019
Citations: 11	License type: CC BY 4.0

Affiliation: University of Ottawa, Universidade Federal do ABC

Abstract

The sarcolemmal membrane associated proteins (SLMAPs) belong to the super family of tail anchored membrane proteins which serve diverse roles in biology including cell growth, protein trafficking and ion channel regulation. Mutations in human SLMAP have been linked to Brugada syndrome with putative deficits in trafficking of the sodium channel (Nav1.5) to the cell membrane resulting in aberrant electrical activity and heart function. Three main SLMAP isoforms (SLMAP1 (35 kDa), SLMAP2 (45 kDa), and SLMAP3 (91 kDa)) are expressed in myocardium but their precise role remains to be defined. Here we generated transgenic (Tg) mice with cardiac-specific expression of the SLMAP3 isoform during postnatal development which present with a significant decrease (20%) in fractional shortening and (11%) in cardiac output at 5 weeks of age. There was a lack of any notable cardiac remodeling (hypertrophy, fibrosis or fetal gene activation) in Tg hearts but the electrocardiogram indicated a significant increase (14%) in the PR interval and a decrease (43%) in the R amplitude. Western blot analysis indicated a selective and significant decrease (55%) in protein levels of Nav1.5 while 45% drop in its transcript levels were detectable by qRT-PCR. Significant decreases in the protein and transcript levels of the calcium transport system of the sarcoplasmic reticulum (SERCA2a/PLN) were also evident in Tg hearts. These data reveal a novel role for SLMAP3 in the selective regulation of important ion transport proteins at the level of gene expression and suggest that it may be a unique target in cardiovascular function and disease.

Highlights

Ion channels and transporters located in sarcolemma (SL) and sarcoplasmic reticulum (SR) are key regulators of the electrical activity in cardiomyocytes and dictate their contraction and relaxation [1,2,3]
Mice were generated in a B6D2F1 genetic background and progeny screened for SLMAP3 transgene copies by qRT-PCR and protein levels of the endogenous (~91 kDa) and 6-myc SLMAP3 (~110 kDa), which were assessed by western blotting with anti-sarcolemmal membrane-associated protein (SLMAP) or anti-Myc antibodies
Mutations in human SLMAP have been shown to lead to Brugada syndrome due to potential defective trafficking of the alpha 1 subunit (Nav1.5) of the sodium channel to the sarcolemma this needs to be confirmed [19]

Summary

Introduction

Ion channels and transporters located in sarcolemma (SL) and sarcoplasmic reticulum (SR) are key regulators of the electrical activity in cardiomyocytes and dictate their contraction and relaxation [1,2,3]. The increased intracellular Ca2+ activates the myofilaments leading to myocyte contraction [2,4]. Repolarization is initiated by potassium channels and coincides with the removal of cytosolic Ca2+ back in to the SR by the Ca2+-ATPase. Other routes of Ca2+ removal include Na+/Ca2+ exchanger (NCX1)and the sarcolemmal Ca2+-ATPase. Alteration in the activity of these ion channels and transporters leads to abnormal electrical activity and changes in contraction/relaxation resulting in cardiac dysfunction [5,6,7,8,9,10,11]

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