Review article
Regulation of the cardiac Na+/H+ exchanger in health and disease

https://doi.org/10.1016/j.yjmcc.2013.02.007Get rights and content

Abstract

The Na+ gradient produced across the cardiac sarcolemma by the ATP-dependent Na+-pump is a constant source of energy for Na+-dependent transporters. The plasma membrane Na+/H+ exchanger (NHE) is one such secondary active transporter, regulating intracellular pH, Na+ concentration, and cell volume. NHE1, the major isoform found in the heart, is activated in response to a variety of stimuli such as hormones and mechanical stress. This important characteristic of NHE1 is intimately linked to heart diseases, including maladaptive cardiac hypertrophy and subsequent heart failure, as well as acute ischemic-reperfusion injury. NHE1 activation results in elevation of pH and intracellular Na+ concentration, which potentially enhance downstream signaling cascades in the myocardium. Therefore, in addition to determining the mechanism underlying regulation of NHE1 activity, it is important to understand how the ionic signal produced by NHE1 is transmitted to the downstream targets. Extensive studies have identified many accessory factors that interact with NHE1. Here, we have summarized the recent progress on understanding the molecular mechanism underlying NHE1 regulation and have shown a possible signaling pathway leading to cardiac remodeling, which is initiated from NHE1. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

Highlights

► Stimulation of hormone receptor activates the sarcolemmal NHE1. ► Activation of NHE1 leads to increase in intracellular pH and Na+ concentration. ► Ionic changes via NHE1 can initiate cardiac hypertrophy and heart failure. ► We discuss upstream and downstream signaling pathways of NHE1.

Introduction

The plasma membrane Na+/H+ exchanger (NHE) catalyzes acid extrusion by electroneutral ion exchange, using the energy support provided by Na+–K+-ATPase. The housekeeping isoform NHE1 is a key regulator of intracellular pH (pHi), Na+ concentration, and cell volume in virtually all tissues [1]. In cardiac muscles, intracellular acidosis results in Na+-overload via NHE1, followed by a sustained increase in the cytosolic Ca2 + concentration via cardiac Na+/Ca2 + exchanger. In addition, acidosis itself seriously reduces myofibrilar Ca2 + sensitivity, resulting in contractile dysfunction. Therefore, it is important for cardiac muscles to rapidly remove acid load during contraction, particularly under pathological conditions such as ischemia.

NHE1 has also been implicated in cardiac hypertrophy and chronic heart disease. In various diseased animal models, the NHE1 inhibitor had a highly beneficial effect [2]. The involvement of NHE1 in chronic disease is strongly linked to the finding that NHE1 is activated in response to hormones such as endothelin-1 and norepinephrine, as well as mechanical stress like stretching; these factors are all inducers of cardiac remodeling. In studies on NHE1, 2 fundamental questions arise: 1) How is NHE1 regulated? and 2) What does NHE1 regulate? Many upstream and downstream targets of NHE1 have been identified. In this review, we will briefly summarize the basic knowledge on the NHE1 molecule and then report the recent progress on several accessory factors of NHE1, which play critical roles in the regulation of NHE1 activity. Finally, we will discuss the amplification of downstream signaling pathways by NHE1 activation, leading to cardiac remodeling. The structure–function relationship and pathological aspects of this transport system have been extensively reviewed earlier [2], [3], [4], [5], [6], [7], [8], [9]. Interested readers should also refer to these reviews.

Section snippets

Na+/H+ exchanger molecule

In 1989, Sardet et al. first cloned the human Na+/H+ exchanger cDNA by genetic complementation of exchanger-deficient cells [10]. This protein is ubiquitously expressed in all tissues and is now known as NHE1. Since the initial identification of NHE1, 9 isoforms have been discovered, referred to as NHE1–NHE9. NHE1–NHE5 are expressed in the plasma membrane, while NHE6–NHE9 localize to the intracellular membranes such as the Golgi apparatus and endosomes [11]. In contrast to the ubiquitous

Regulation of NHE1

NHE1 is activated in response to various extracellular stimuli. This is thought to occur via the interaction of accessory proteins or bioactive substances with the cytoplasmic domain by a phosphorylation-dependent or phosphorylation-independent mechanism. The cytoplasmic domain of NHE1 has been reported to interact with various proteins, including Ca2 +-binding proteins, protein kinases, phosphatases, and cytoskeletal proteins [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. In

Involvement of NHE1 in cardiac disease

There is ample evidence suggesting that NHE1 mediates cardiac injuries induced by ischemia-reperfusion [92]. This is based on studies indicating that NHE1 inhibitors such as cariporide [93], eniporide [94] and zoniporide [95] afford significant protection against these injuries in many animal models and in patients undergoing coronary interventions [96], [97]. Evidence that mice lacking the Nhe1 gene are resistant to ischemia-reperfusion injury further supports the potential involvement of NHE1

Downstream signaling leading to cardiac hypertrophy and heart failure

NHE1 is activated in response to various hormones such as endothelin-1 [108], angiotensin II [109], and α1-adrenergic agonists [110], as well as mechanical stimuli like stretching [111], [112], [113], all of which contribute to cardiac remodeling [2], [108], [114]. Stretch-induced NHE1 activation may occur via hormone receptor activation caused by an autocrine–paracrine mechanism [115]. NHE1 couples H+ efflux to Na+ influx under the driving force of a Na+ gradient formed by the Na+-pump.

Conclusion

A large body of evidence has indicated the contribution of NHE1 in cardiac remodeling and heart failure. In Fig. 3, we have summarized the relationship between NHE1 and its upstream and downstream target proteins leading to cardiac hypertrophy. Activation of NHE1 can modulate Ca2 +-dependent prohypertrophic signaling via changes in [Na+]i and pHi. The cytoplasmic domain of NHE1 appears to play 2 important roles in this regulation: 1) regulation of NHE1 activity by receiving upstream input

Acknowledgments

We thank Dr. Yuji Arai for the production of transgenic mice, and Dr. Soichi Takeda for crystal structure determination. We also thank all collaborators who participated in our studies. The studies cited from the authors' group are supported by grants from the Ministry of Health, Labour and Welfare; the Ministry of Education, Culture, Sports, Science and Technology; and the National Institute of Biomedical Innovation.

Conflicts of interest

None.

References (141)

  • E. Miyazaki et al.

    NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell

    J Biol Chem

    (2001)
  • P. Fafournoux et al.

    Evidence that Na+/H+ exchanger isoforms NHE1 and NHE3 exist as stable dimers in membranes with a high degree of specificity for homodimers

    J Biol Chem

    (1994)
  • K. Moncoq et al.

    Dimeric structure of human Na+/H+ exchanger isoform 1 overproduced in Saccharomyces cerevisiae

    J Biol Chem

    (2008)
  • S. Wakabayashi et al.

    Kinetic dissection of two distinct proton binding sites in Na+/H+ exchangers by measurement of reverse mode reaction

    J Biol Chem

    (2003)
  • S. Wakabayashi et al.

    Mutations of Arg440 and Gly455/Gly456 oppositely change pH sensing of Na+/H+ exchanger 1

    J Biol Chem

    (2003)
  • B. Bertrand et al.

    The Na+/H+ exchanger isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins. Identification and characterization of calmodulin-binding sites

    J Biol Chem

    (1994)
  • S.P. Denker et al.

    Direct binding of the Na–H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H+ translocation

    Mol Cell

    (2000)
  • S. Lehoux et al.

    14-3-3 binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange

    J Biol Chem

    (2001)
  • X. Li et al.

    Carbonic anhydrase II binds to and enhances activity of the Na+/H+ exchanger

    J Biol Chem

    (2002)
  • W. Yan et al.

    The Nck-interacting kinase (NIK) phosphorylates the Na+–H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor

    J Biol Chem

    (2001)
  • A. Simonin et al.

    Nedd4-1 and beta-arrestin-1 are key regulators of Na+/H+ exchanger 1 ubiquitylation, endocytosis, and function

    J Biol Chem

    (2010)
  • Y.S. Jung et al.

    Physical interactions and functional coupling between Daxx and sodium hydrogen exchanger 1 in ischemic cell death

    J Biol Chem

    (2008)
  • P. Karki et al.

    B-Raf associates with and activates the NHE1 isoform of the Na+/H+ exchanger

    J Biol Chem

    (2011)
  • E. Takahashi et al.

    p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1

    J Biol Chem

    (1999)
  • M.E. Meima et al.

    The sodium-hydrogen exchanger NHE1 is an Akt substrate necessary for actin filament reorganization by growth factors

    J Biol Chem

    (2009)
  • M.E. Malo et al.

    Mitogen-activated protein kinase-dependent activation of the Na+/H+ exchanger is mediated through phosphorylation of amino acids Ser770 and Ser771

    J Biol Chem

    (2007)
  • M.R. Barroso et al.

    A novel Ca2 +-binding protein, p22, is required for constitutive membrane traffic

    J Biol Chem

    (1996)
  • T. Pang et al.

    Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger

    J Biol Chem

    (2002)
  • J. Mailander et al.

    Human homolog of mouse tescalcin associates with Na+/H+ exchanger type-1

    FEBS Lett

    (2001)
  • M. Mishima et al.

    Solution structure of the cytoplasmic region of Na+/H+ exchanger 1 complexed with essential cofactor calcineurin B homologous protein 1

    J Biol Chem

    (2007)
  • T. Pang et al.

    Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers

    J Biol Chem

    (2001)
  • H.C. Zaun et al.

    Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform

    J Biol Chem

    (2008)
  • H.C. Zaun et al.

    N-myristoylation and Ca2 + binding of calcineurin B homologous protein CHP3 are required to enhance Na+/H+ exchanger NHE1 half-life and activity at the plasma membrane

    J Biol Chem

    (2012)
  • C.W. Taylor

    Controlling calcium entry

    Cell

    (2002)
  • S. Wakabayashi et al.

    Mutation of calmodulin-binding site renders the Na+/H+ exchanger (NHE1) highly H+-sensitive and Ca2 + regulation-defective

    J Biol Chem

    (1994)
  • S. Wakabayashi et al.

    Growth factor activation and “H+-sensing” of the Na+/H+ exchanger isoform 1 (NHE1). Evidence for an additional mechanism not requiring direct phosphorylation

    J Biol Chem

    (1994)
  • S. Koster et al.

    Structure of human Na+/H+ exchanger NHE1 regulatory region in complex with calmodulin and Ca2 +

    J Biol Chem

    (2011)
  • Y.V. Mukhin et al.

    Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2 +/calmodulin

    J Biol Chem

    (2001)
  • B.G. Abu Jawdeh et al.

    Phosphoinositide binding differentially regulates NHE1 Na+/H+ exchanger-dependent proximal tubule cell survival

    J Biol Chem

    (2011)
  • S. Mohan et al.

    NHE3 activity is dependent on direct phosphoinositide binding at the N terminus of its intracellular cytosolic region

    J Biol Chem

    (2010)
  • S. Wakabayashi et al.

    Novel phorbol ester-binding motif mediates hormonal activation of Na+/H+ exchanger

    J Biol Chem

    (2010)
  • A.R. Cook et al.

    Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress?

    J Mol Cell Cardiol

    (2009)
  • S. Wakabayashi et al.

    Molecular physiology of vertebrate Na+/H+ exchangers

    Physiol Rev

    (1997)
  • B.L. Lee et al.

    Structural analysis of the Na+/H+ exchanger isoform 1 (NHE1) using the divide and conquer approach

    Biochem Cell Biol

    (2011)
  • J. Orlowski et al.

    Diversity of the mammalian sodium/proton exchanger SLC9 gene family

    Pflugers Arch

    (2004)
  • M. Donowitz et al.

    Regulatory binding partners and complexes of NHE3

    Physiol Rev

    (2007)
  • J.R. Casey et al.

    Sensors and regulators of intracellular pH

    Nat Rev Mol Cell Biol

    (2010)
  • E. Boedtkjer et al.

    Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy

    Curr Pharm Des

    (2012)
  • R. Ohgaki et al.

    Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions

    Biochemistry (Mosc)

    (2011)
  • C.L. Brett et al.

    Evolutionary origins of eukaryotic sodium/proton exchangers

    Am J Physiol Cell Physiol

    (2005)
  • Cited by (0)

    View full text