β-Catenin Controls the Electrophysiologic Properties of Skeletal Muscle Cells by Regulating the α2 Isoform of Na+/K+-ATPase.

Congying Zhao,Lu Xu,Shanshan Mao,Peifang Jiang,Yi Zhang,Yonglin Yu,Feng Gao,Kewen Jiang,Lihua Jiang,Weiqin Zhang,Guoxia Sheng,Jue Shen

doi:10.3389/fnins.2019.00831

Abstract

β-Catenin is a key component of the canonical Wnt signaling pathway. It has been shown to have an important role in formation of the neuromuscular junction. Our previous studies showed that in the absence of β-catenin, the resting membrane potential (RMP) is depolarized in muscle cells and expression of the α2 subunit of sodium/potassium adenosine triphosphatase (α2NKA) is reduced. To understand the underlying mechanisms, we investigated the electrophysiologic properties of a primary cell line derived from mouse myoblasts (C2C12 cells) that were transfected with small-interfering RNAs and over-expressed plasmids targeting β-catenin. We found that the RMP was depolarized in β-catenin knocked-down C2C12 cells and was unchanged in β-catenin over-expressed muscle cells. An action potential (AP) was not released by knockdown or over-expression of β-catenin. α2NKA expression was reduced by β-catenin knockdown, and increased by β-catenin over-expression. We showed that β-catenin could interact physically with α2NKA (but not with α1NKA) in muscle cells. NKA activity and α2NKA content in the cell membranes of skeletal muscle cells were modulated positively by β-catenin. These results suggested that β-catenin (at least in part) regulates the RMP and AP in muscle cells, and does so by regulating α2NKA.

Highlights

NKA activity and α2NKA content in the cell membranes of skeletal muscle cells were modulated positively by β-catenin. These results suggested that β-catenin regulates the resting membrane potential (RMP) and action potential (AP) in muscle cells, and does so by regulating α2NKA
We showed that β-catenin plays a part in the RMP and action potential (AP) of skeletal muscle cells at the neuromuscular junction (NMJ)
We provided further evidence that β-catenin is crucial for maintaining the RMP and evoking the AP in skeletal muscle cells

Summary

Introduction

Β-Catenin is a crucial downstream component of the Wnt signaling pathway. β-Catenin translocates to the nucleus and subsequently regulates target–gene transcription (Molenaar et al, 1996; Hecht et al, 2000). β-Catenin binds to the cytoplasmic domain of α-catenin and cadherins, where it participates in cell adherence and organization of the actin cytoskeleton (Nelson and Nusse, 2004). β-Catenin promotes cell proliferation and tissue expansion, it affects the fate and final differentiation of cells after cell division. β-Catenin is associated with disorders β-Catenin Controls Electrophysiological Properties via α2NKA caused by abnormal development and some tumors (Chilosi et al, 2003; Varallo et al, 2003; Jamieson et al, 2004; Batlle et al, 2005). Studies have suggested that Wnt/β-catenin signaling is involved in Alzheimer’s disease (Caricasole et al, 2003; Zhao et al, 2005), schizophrenia (Singh et al, 2010), and emotional disorders (Lovestone et al, 2007). Agrin is released by motor neurons and binds to low-density lipoprotein receptor-related protein (LRP)-4 and activates muscle-specific kinase (MuSK). We showed that β-catenin is crucial for maintenance of the resting membrane potential (RMP) of skeletal muscle cells, and that its lack of expression can induce marked reductions in expression of the α2 subunit of sodium/potassium adenosine triphosphatase (α2NKA) (Zhao et al, 2014)

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Conclusion