Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FXYD1 (Phospholemman)

  • Kyung Chan Park
  • Davor Pavlovic
  • Michael J. Shattock
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101757

Synonyms

Historical Background

Phospholemman (PLM) is a 72-amino-acid type I single-span membrane protein, belonging to the FXYD (pronounced “fix-it”) family of ion transport regulators. These smallmembrane proteins are tissue-specific regulators of the Na/K ATPase (Na/K pump or NKA). PLM is predominantly expressed in striated (cardiac and skeletal) and smooth muscle (Bogaev et al. 2001; Rembold et al. 2005). However, it is also detectable to a lesser extent in the kidney (Wetzel and Sweadner 2003), liver (Bogaev et al. 2001), cerebellum, and choroid plexus (Feschenko et al. 2003).

PLM was first identified in canine and guinea pig myocardium as a 15 kDa sarcolemmal protein and was later shown to be the principle sarcolemmal substrate for protein kinases A and C (PKA and PKC) (Presti et al. 1985a, b). At the time, the correlation between PLM phosphorylation and PKA-induced positive inotropy led Prest and colleagues to speculate that this small protein may be involved in mediating the effects of β-adrenoceptor stimulation on cardiac contractile force. However, although PLM was purified and cloned more than two decades ago (Palmer et al. 1991), its real physiological function has only become clear in recent years. After its discovery, this 15 kDa protein was sequenced using Edman degradation and was shown to be 72 amino acids in length; the acidic extracellular NH2 terminal consists of 17 amino acids, the hydrophobic membrane-spanning segment 20 amino acids, and the basic intracellular COOH terminus 35 amino acids in length. The phosphorylation sites for PKA and PKC were confirmed to be serines 62, 63, 68 and threonine 69 at the COOH terminus (Palmer et al. 1991). Due to its sarcolemmal localization and multiple phosphorylation sites, it was named “phospholemman.”

Initial studies suggested PLM to be involved in cell volume regulation, due to its ability when overexpressed, to form channels in lipid membranes selective for taurine, an osmolyte in eukaryotic cells (Moorman et al. 1995). However, inducing an osmotic challenge to isolated cardiac myocytes, from both PLM wild-type (PLMWT) and knockout (PLMKO) mice, results in equal osmotic swelling (Bell et al. 2009), demonstrating that PLM may not be essential in regulating cell volume. The early studies suggesting an ability of clusters of PLM to form nonselective ion channels may have simply been an artifact of overexpressing large amounts of a small single-span transmembrane protein. More recent reports have demonstrated both a physical and functional association of PLM with the Na/K ATPase. In particular it is now well established that PLM, along with the other members of the FXYD family, is expressed in a tissue-specific manner and that they associate with, and regulate, the transport properties of the Na/K ATPase (Geering 2006).

The FXYD Family of Ion Transport Regulators

The FXYD family of small membrane, tissue-specific, ion transport regulators were defined over 15 years ago by Sweadner and Rael in 2000. In their membrane-spanning domains, members of this family have a 35-amino-acid sequence that is conserved across species. The family was named “FXYD” based on the initial amino acid codes of this 35-amino-acid signature motif: phenylalanine-X-tyrosine-aspartate (the “X” is usually tyrosine but can also be glutamate, threonine, or histidine) (Sweadner and Rael 2000). In mammals, the FXYD family comprises of seven members: FXYD1, otherwise known as phospholemman (Palmer et al. 1991); FXYD2, γ-subunit of the Na/K pump (Mercer et al. 1993); FXYD3, mammary tumour marker, Mat-8 (Morrison et al. 1995); FXYD4, corticosteroid hormone-induced factor, CHIF (Attali et al. 1995); FXYD5, related to ion channel RIC or dysadherin (Fu and Kamps 1997); FXYD6, phosphohippolin (Yamaguchi et al. 2001); and FXYD7 (Beguin et al. 2002).

All FXYD proteins are type I single-span membrane proteins with a cytosolic COOH terminus. With the exception of FXYD5, which has 178 amino acids due to an extension at its NH2 terminus, all proteins of the FXYD family have 61–95 amino acids (Geering 2006). Although FXYD proteins were identified more than a decade ago, their function had been unknown until recent years. Initial studies on several of the FXYD proteins (Attali et al. 1995; Morrison et al. 1995; Fu and Kamps 1997), including FXYD1 (Moorman et al. 1992), provided evidence to show that overexpression in Xenopus laevis oocytes induces ion-specific conductances. However, these lines of evidence were controversial since overexpression of PLM is now known to cause oligomerization of excess PLM in the cell membrane (leading to the initial interpretation that PLM was a “channel”) (Bossuyt et al. 2006; Garty and Karlish 2006). Findings from these early studies reporting that overexpression leads to ion channel formation were superseded when Beguin et al. (1997) demonstrated that endogenous FXYD2 is in fact spatially associated with the renal Na/K ATPase and that when assessed by patch-clamping (the most direct measure of electrogenic ion transport), FXYD2 modulated the Na/K pump’s activity (Beguin et al. 1997). Since the study by Beguin et al., considerable research effort has been focussed on determining whether any other of the FXYD protein family modulates Na/K pump activity. It is now known that at least five of the seven FXYD proteins associate with, and modulate, the Na/K ATPase by modifying its substrate affinities (K m ) and maximum transport rate (V max ) (Geering 2006).

Phospholemman (FXYD1)

Overview

Phospholemman (PLM or FXYD1) is predominantly expressed in muscle: cardiac, skeletal, and smooth (Bogaev et al. 2001; Rembold et al. 2005). It is currently well established that PLM has a key role in regulating Na/K ATPase activity, both in heart and skeletal muscle via a number of mechanisms and posttranslational modifications (for recent reviews see Pavlovic et al. 2013a, b; Pirkmajer and Chibalin 2016). Its role is analogous to that of phospholamban [which regulates the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a)]. Because the Na/K ATPase has a critical role in maintaining cellular homeostasis and in participating in numerous specialized physiological processes, pump regulation has been an intense field of research for the past two decades. Though there are some well-established regulators of NKA [e.g., substrate concentration and hormonal regulation, reviewed extensively by Therien and Blostein (2000)], given the importance of the Na/K pump in a plethora of processes, the discovery of the FXYD proteins as new regulators of this pump has prompted substantial research in this field. The vast majority of reports on FXYD1 are on those studying the Na/K pump, with particular emphasis on the cardiac Na/K pump. However, it should be noted that there is also evidence suggesting PLM may regulate activity of the cardiac Na/Ca exchanger, with some reports also implicating a possible role in regulation of L-type Ca channel activity (see below).

Regulation of the Na/K ATPase

Discovered by Jens C. Skou in 1957, the Na/K pump is a heterodimer belonging to the P-type ATPase superfamily and is a ubiquitous integral membrane protein responsible for the active transport of Na and K ions across the plasma membrane of almost every eukaryotic cell. The seminal study by Crambert et al. (2002) demonstrated that PLM is physically associated with this pump and that it modulates its activity. NKA consists of a glycosylated β-subunit which helps traffic the pump to the plasma membrane (three isoforms; β1, β2, and β3), and a catalytic α-subunit which binds and hydrolyses ATP, as well as transporting Na and K cations (four isoforms; α1, α2, α3, and α4) (Kaplan 2002). The 2002 Crambert study showed that PLM coimmunoprecipitated with the α1-β pump complex in native cardiac and skeletal muscle (NB: α1 is the predominantly expressed form across all cell types). More recent evidence provided using crosslinking (Lindzen et al. 2006), fluorescence resonance energy transfer (FRET) (Bossuyt et al. 2006), and X-ray crystallography (Morth et al. 2007) support Crambert and colleagues’ earlier findings of a physical interaction between PLM and the α-subunit of NKA.

The three-dimensional structure of PLM was elucidated in 2007 by utilizing NMR-spectroscopy on purified PLM in SDS-detergent micelles (Teriete et al. 2007). This study showed that PLM is organized into four α-helices, H1–H4 (Figs. 1 and 2). Helix H4 of PLM is positively charged. When PLM is unphosphorylated, it is thought that H4 adheres to the negatively charged cytoplasmic domain of the Na/K pump. The current working hypothesis is that upon PLM phosphorylation, negative charges on H4 may act to weaken the molecular interaction between PLM and the Na/K pump, thus affecting pump function (Pavlovic et al. 2013a; Mishra et al. 2015). A recent report from the laboratory of Steven Karlish has provided further insights into the molecular and kinetic mechanisms by which PLM regulates the Na/K pump, whereby the unphosphorylated and phosphorylated forms of PLM appear to have differential effects on the Na/K pump’s conformational states and Na binding affinity (Mishra et al. 2015).
FXYD1 (Phospholemman), Fig. 1

Basic structure of phospholemman (PLM). PLM is organized into four α-helices (H). H1 is located extracellularly (Asp12 to Gln17); H2 forms the membrane-spanning domain (Ile19 to Leu36); the cytoplasmic domain consists of two helices, H3 (Ser37 to Lys43), and H4 (Thr59 to Ser68). The phosphorylation sites are located in H4. The gray box represents the plasma membrane (Adapted with permission from Teriete et al. (2007), Copyright 2016 American Chemical Society)

FXYD1 (Phospholemman), Fig. 2

Molecular model of the three-dimensional structure of phospholemman (PLM) determined by NMR-spectroscopy. (a) Basic side chains are shown in blue, acidic side chains in red, and apolar side chains in yellow. Ser62, Ser63, Ser68, and Thr69 in the cytoplasmic helix are in green. (b) The structure is shown after a 90° rotation around the y-axis (relative to the plasma membrane). The amino acid residues in the membrane-spanning domain marked yellow are those predicted to interact with the α-subunit of the Na/K ATPase (Na/K pump): Gly20, Ala24, Gly25, Phe28, Gly31, and Val35. (c) The structure is shown after a 90° rotation around the x-axis (relative to the plasma membrane) from the structure b (Adapted with permission from Teriete et al. 2007, Copyright 2016 American Chemical Society)

It is currently well established that PLM regulates activity of the Na/K pump in multiple cell types. In the heart, PLM is the primary sarcolemmal substrate for PKA and PKC phosphorylation (Presti et al. 1985b). Under basal conditions, PLM is mostly, but not entirely, phosphorylated (~38% unphosphorylated, Fuller et al. 2009) and a tonic inhibition is exerted on the Na/K pump by reducing its substrate affinity (Despa et al. 2005; Han et al. 2006) and/or V max (Pavlovic et al. 2007; Bossuyt et al. 2009). Kinase-mediated phosphorylation of PLM on ser68 (by PKA or PKC) or ser63 and thr69 (by PKC) relieves this inhibition (Despa et al. 2005; Pavlovic et al. 2007, 2013b). In vitro electrophysiological evidence has shown that PLM phosphorylation mediates the stimulatory effects imposed on the Na/K pump via β-adrenergic stimulation in the heart (Despa et al. 2005). In vivo evidence from the PLM knockout mouse demonstrates depressed contractile function (in vivo conductance catheters and Langendorff-perfusions) with increased Na/K pump activity (inorganic phosphate assays) (Bell et al. 2008). Moreover, data from patch-clamp studies have shown increased Na/K pump currents in PLM-knockout mouse ventricular myocytes (Pavlovic et al. 2007). Collectively, these findings are consistent with the hypothesis that PLM modulates Na/K pump activity, which has an indirect effect on Ca load (via Na/Ca exchange) and hence contractility (Pavlovic et al. 2013b; Boguslavskyi et al. 2014). It should be noted, however, that phosphoregulation of PLM is not confined to adrenergic receptor signaling alone. There is evidence in field-stimulated cardiac myocytes that nitric oxide activates the Na/K pump via PKCε-induced PLM phosphorylation at Ser63 and Ser68 (see Pavlovic et al. 2013a for review). Signaling pathways that are known to regulate the Na/K pump via PLM are summarized in Fig. 3.
FXYD1 (Phospholemman), Fig. 3

The variety of signaling pathways by which Na/K ATPase (Na/K pump) activity is regulated via phospholemman (PLM) phosphorylation. Phosphoregulation of PLM is mediated via protein kinase A (PKA) and protein kinase C (PKC), in addition to phosphatase activity via protein phosphatase-1 (PP-1) and protein phosphatase-2a (PP-2A). Stimulatory signals are denoted by pluses while inhibitory signals are denoted by minuses. AR adrenergic receptor, ET A endothelin-A receptor, NOS nitric oxide synthase, NO nitric oxide, PLC phospholipase C, PIP2 phosphatidylinositol 4,5-bisphosphate, IP3 inositol 1,4,5-trisphosphate, DAG diacylglycerol, PKA protein kinase A, PKC protein kinase C, PP protein phosphatase (Reprinted with permission from Pavlovic et al. 2013, Copyright 2016 Elsevier)

In addition, recent findings have shown that PLM is also regulated by a number of other posttranslational modifications in addition to phosphorylation: palmitoylation (Tulloch et al. 2011) and glutathionylation (Bibert et al. 2011). While PLM phosphorylation or glutathionylation activates the Na/K pump, palmitoylation of PLM reduces pump activity (see Fig. 4 for an overview). The functional significance of palmitoylation and glutathionylation is yet to be clearly demonstrated (for details, see Howie et al. 2013).
FXYD1 (Phospholemman), Fig. 4

Summary of the posttranslational modifications of phospholemman (PLM) and their functional effects on activity of the Na/K ATPase (Na pump). The functional effect of the posttranslational modification in question is marked green for Na/K pump stimulation, red for inhibition, and gray for where the effect is currently unknown. The amino acid residues involved are in parentheses (Reprinted with permission from Pavlovic et al. 2013, Copyright 2016 Elsevier)

Regulation of the Na/Ca Exchanger

There is a growing body of evidence for a functional association of PLM and the cardiac Na/Ca exchanger protein (NCX). Central to this is the work from the laboratory of Joseph Cheung. NCX is a membrane-bound protein catalyzing the trans-sarcolemmal transport of three Na ions in exchange for one Ca ion. This process is driven by the energy of the prevailing Na gradient. Unlike the regulation of NKA, PLM phosphorylation at Ser68 has been reported to inhibit the cardiac Na/Ca exchanger (NCX1) (see Cheung et al. 2010 for review). In 2002, the Cheung group first reported that PLM modulates NCX1 activity in adult rat ventricular myocytes (Zhang et al. 2003). In this study, PLM was overexpressed using adenovirus-mediated gene transfer; NCX1 activity was assessed by measuring the half-time of relaxation from caffeine-induced contracture (a surrogate marker of forward NCX1 activity) and by electrophysiological measurements on the reverse-mode NCX1 current (3 Na out:1 Ca in). Their results showed that PLM overexpression resulted in a prolonged half-time of relaxation to caffeine with a significantly reduced NCX1 current, suggesting inhibition of Na/Ca exchange. A subsequent report where PLM was downregulated showed the opposite effect to PLM overexpression (i.e., stimulation of NCX1) (Mirza et al. 2004). Because PLM appears to inhibit both the influx and efflux of Ca by NCX1, the change in intracellular Na (secondary to changes in Na/K pump activity via PLM) cannot account for these findings (Garty and Karlish 2006). Furthermore, Zhang et al. (2003) showed that PLM and NCX1 colocalize at the plasma membrane and transverse-tubule using confocal microscopy. However, no interaction can be detected between PLM and NCX1 when assessed using FRET (Bossuyt et al. 2006).

Regulation of the L-Type Ca Channel

A small number of reports have suggested that overexpressed PLM may modulate cardiac L-type Ca channel (LTCC) activity. The LTCC is a voltage-gated Ca channel, which in the heart, opens upon membrane depolarization resulting in an inward Ca current (I Ca,L ) and a subsequent increase in intracellular Ca. This Ca influx is a critical step in initiating cardiac contraction by triggering the release of a larger amount of Ca from intracellular stores via the process of calcium-induced calcium-release. The first report of a potential role for PLM in regulating LTCC activity came from the laboratory of Blaise Peterson in 2010 (Wang et al. 2010), with a more recent collaborative study published between Blaise Peterson and Joseph Cheung (Zhang et al. 2015). Wang et al. (2010) found that Cav1.2 channels (L-type Ca channel) coimmunoprecipitated with PLM from guinea pig ventricular myocytes. Furthermore, in transfected HEK293 cells, PLM was found to modulate a number of important gating processes of Cav1.2 channels but not Cav2.1 (P/Q-type) or Cav2.2 (N-type) channels. For example, co-expression of PLM with Cav2.1 slowed deactivation of this Ca channel in a time- and voltage-dependent manner. This, potentially, could result in greater Ca entry during the repolarization phase of the cardiac action potential (Wang et al. 2010). Further work will be required to confirm and characterize any interaction between PLM and L-type Ca channels.

PLM Regulation in Disease

There is a large body of literature investigating the regulation of PLM in disease, specifically of that in the heart. Despa and colleagues demonstrated in 2008 that during β-adrenergic receptor (β-AR) stimulation, PLM phosphorylation at Ser68 leads to increased Na/K pump activity and thereby attenuates Na channel-mediated Na overload. In PLM knockout (PLMKO) isolated cardiac myocytes, absence of this intracellular Na regulatory mechanism leads to Ca overload and thus an increased propensity for spontaneous Ca transients and contractions (Despa et al. 2008). Thus, PLM acts to protect the heart from Ca overload and triggered arrhythmias by preventing Na overload. Of note are the observations that PLM Ser68 phosphorylation is reduced in mouse models of heart failure (Boguslavskyi et al. 2014) as well as in human heart failure (El-Armouche et al. 2011).

In a knockin mouse model (PLM3SA) whereby PLM was rendered unphosphorylatable (Ser63, 68, and 69 mutated to alanines), Na/K pump activity was reduced versus wild-type (WT) littermates (Boguslavskyi et al. 2014). The reduction of Na/K pump activity in PLM3SA mice was subsequently found to lead to decreased Na/Ca exchange activity and increased diastolic Ca (i.e., diastolic dysfunction). Furthermore, PLM3SA mice subjected to aortic constriction (model of heart failure) developed greater Na overload, contractile dysfunction and exacerbated adverse hypertrophic remodeling versus WT (Boguslavskyi et al. 2014).

Collectively, PLM phosphorylation appears to protect the heart from arrhythmias, contractile dysfunction, and adverse cardiac remodeling by limiting intracellular Na and Ca overload.

Summary

Phospholemman (PLM) is a small membrane protein which is predominantly expressed in muscle, belonging to the FXYD family of ion transport regulators. These proteins are tissue-specific regulators of the Na/K ATPase (Na/K pump), a ubiquitous integral membrane protein that has a critical role in maintaining cellular homeostasis, as well as participating in numerous specialized physiological processes. Under basal conditions, PLM exerts a tonic inhibition on the Na/K pump by reducing its substrate affinity and/or maximal transport rate. PLM is phosphoregulated and this tonic inhibition is relieved upon kinase-mediated phosphorylation via a myriad of signaling pathways. In disease, PLM phosphorylation is decreased and this contributes to Na and Ca overload, thereby leading to arrhythmias, contractile dysfunction, and maladaptive hypertrophy in the heart. Recent work has also demonstrated that PLM is subject to a number of other post-translational modifications, including glutathionylation and palmitoylation, each having a different effect on Na/K pump activity.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kyung Chan Park
    • 1
  • Davor Pavlovic
    • 2
  • Michael J. Shattock
    • 1
  1. 1.British Heart Foundation Centre of Research Excellence, Cardiovascular DivisionKing’s College London, The Rayne Institute, St Thomas’ HospitalLondonUK
  2. 2.Institute of Cardiovascular SciencesUniversity of BirminghamBirminghamUK