Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications

doi:10.1016/j.pathophys.2007.09.008

Pathophysiology

Volume 14, Issues 3–4, December 2007, Pages 171-181

https://doi.org/10.1016/j.pathophys.2007.09.008 Get rights and content

Abstract

We have previously shown that ouabain and other cardiotonic steroids interact with the plasmalemmal Na/K-ATPase and cause a time and dose dependent endocytosis of the Na/K-ATPase. This endocytosis is demonstrable using fluorescence imaging as well as conventional biochemical and biophysical cell separation methods. In proximal tubule cells, this process appears to regulate the density of basolateral Na/K-ATPase expression directly as well as indirectly modulate transepithelial sodium transport.

Work with genetic manipulations, as well as pharmacological agents with cell culture models, have demonstrated that the cardiotonic steroid stimulated endocytosis of the plasmalemmal Na/K-ATPase requires caveolin and clathrin as well as the activation of c-Src, transactivation of the EGFR and activation of PI3K. Interestingly c-Src, EGFR and ERK1/2 all appear to be endocytosed along with the plasmalemmal Na/K-ATPase. These observations suggest a close analogy between a subset of plasmalemmal Na/K-ATPase and signaling companions with conventional receptor tyrosine kinases. While further studies are necessary to delineate the role of this endocytosis in the generation as well as the limit of signal transduction through the Na/K-ATPase signal cascade, we propose that it has an important role in the regulation of renal sodium handling as well as other important processes.

Introduction

Endocytosis is the vesicle-mediated process used by all cells to internalize extracellular macromolecules and plasma membrane components, and is responsible for the transport of proteins between various compartments of the secretory and endocytic systems. It can be broadly divided into two categories based on the material internalized. Phagocytosis (or cell eating) refers to the internalization of large particles (>200 nm). Pinocytosis (or cell drinking) refers to the internalization of extracellular medium and may occur through four basic mechanisms: clathrin-dependent endocytosis, caveolae-mediated endocytosis, macropinocytosis, and dynamin- and clathrin-independent endocytosis [1]. Although there are several additional types of pinocytosis which have recently been described (e.g., macropinocytosis and non-dynamin mediated pinocytosis [2], [3], [4]), clathrin and caveolin mediated endocytosis are the best described endocytosis pathways.

Section snippets

Mechanisms of endocytosis

Clathrin-coated vesicles are responsible for receptor-mediated endocytosis at the plasma membrane and sorting of proteins at the trans-Golgi network (TGN), and found associated with the cell membrane, the TGN, and on some endosomes [5], [6], [7]. At the plasma membrane, clathrin-mediated internalization is initiated by the self-assembly of clathrin lattice formation to provide an organizing structure. The formation of clathrin coated pits is triggered by the heterotetrameric adaptor complex

Endocytosis and signal transduction

Endocytosis of cell surface receptors is an important regulatory event in signal transduction. The classic concept of receptor downregulation by endocytosis has been established over the past several decades. In general, receptor-mediated endocytosis results in internalization of the receptor and ultimate destruction of the receptor in lysosomes. In this situation, the endocytosis is part of a negative feedback loop meant to attenuate or minimize the signal associated with receptor activation

Na/K-ATPase: an ion pump and a signal transducer

The Na/K-ATPase was first discovered as the molecular machine for the ATP-dependent and -coupled transport of Na⁺ and K⁺ across the plasma membranes of all eukaryotic cells [56], [57]. Na/K-ATPase is a heterodimeric membrane protein that belongs to the type II class of P-type ATPases and consists of two noncovalently linked α and β subunits [57], [58], [59]. The α subunit is considered as the “catalytic subunit” containing the binding sites for ATP, ouabain, and other ligands. The β subunit is

Endocytosis of the Na/K-ATPase in the regulation of renal sodium excretion

The regulation of renal tubule epithelial cell sodium transport by endocytosis of the Na/K-ATPase has been extensively studied. Most of this work has been done in the context of G protein receptor mediated signal transduction induced by dopamine. Dopamine stimulates the Na/K-ATPase trafficking and alters renal tubular epithelial sodium handling by decreasing plasmalemmal Na/K-ATPase content [87], [88], [89], [90]. Endocytosis of the Na/K-ATPase in response to dopamine is triggered by the

Ouabain-induced endocytosis of the Na/K-ATPase in LLC-PK1 cells

In LLC-PK1 cells, acute treatment with low concentrations of ouabain or MBG (≤100 nM) do not cause detectable inhibition of the Na/K-ATPase activity, but chronic treatment with ouabain or MBG causes significant decreases in Na/K-ATPase activity and transepithelial Na⁺ flux without changing in intracellular Na⁺ concentration [99], [100], [101]. Since simply inhibition of the Na/K-ATPase with low extracellular potassium does not produce these effects, we reasoned that other regulatory mechanism(s)

Ouabain regulates sodium handling in renal proximal tubule

Sodium reabsorption in the proximal tubule involves the coupling of apical sodium entry mainly through the NHE3 (sodium/hydrogen exchanger, isoform 3) and basolateral sodium extrusion primarily through the Na/K-ATPase. Accumulated evidence supports the notion that endogenous cardiotonic steroids may cause a physiologically meaningful regulation of transepithelial sodium transport in the proximal tubule. Since low concentrations of ouabain decrease basolateral sodium extrusion by depletion of

Ouabain-Na/K-ATPase in endocytic pathway: signaling termination or propagation?

Binding of ouabain to the receptor Na/K-ATPase signaling complex activates the Na/K-ATPase-bound c-Src, leading to endocytosis of the signaling complex. In early endosomes, functioning as a ion pump, native or endocytosed Na/K-ATPase may regulate endosomal pH by generation of a interior-positive membrane potential [120], [121]. This regulation kept a mild pH (about 6.0) environment in early endosomes, which is sufficient to dissociate most ligand–receptor complexes and facilitate receptor

Physiological implications

Renal adaptation to both volume expansion and hypertension involves a complicated interplay among different hormonal and cellular regulatory mechanisms. Since the finding of proposed endogenous cardiotonic steroids, accumulated evidences have indicated that these steroids might be related to a number of health conditions such as sodium imbalance, chronic renal failure, hypertension, and congestive heart failure. It is known that CTS are elevated during volume expansion. The cardiotonic steroid

Acknowledgement

Portions of this study were supported by grant from American Heart Association Ohio Valley Affiliate.

References (129)

E.S. Seto et al.
When cell biology meets development: endocytic regulation of signaling pathways
Genes Dev.
(2002)
R. Goldman
The effect of cytochalasin B and colchicine on concanavalin A induced vacuolation in mouse peritoneal macrophages
Exp. Cell Res.
(1976)
H.U. Keller
Diacylglycerols and PMA are particularly effective stimulators of fluid pinocytosis in human neutrophils
J. Cell. Physiol.
(1990)
M.E. Graham et al.
Dynamin-dependent and dynamin-independent processes contribute to the regulation of single vesicle release kinetics and quantal size
Proc. Natl. Acad. Sci. U.S.A.
(2002)
J.S. Bonifacino et al.
Coat proteins: shaping membrane transport
Nat. Rev. Mol. Cell Biol.
(2003)
T. Kirchhausen
Three ways to make a vesicle
Nat. Rev. Mol. Cell Biol.
(2000)
F.M. Brodsky et al.
Biological basket weaving: formation and function of clathrin-coated vesicles
Annu. Rev. Cell Dev. Biol.
(2001)
L. Brodin et al.
Sequential steps in clathrin-mediated synaptic vesicle endocytosis
Curr. Opin. Neurobiol.
(2000)
L. DeTulleo et al.
The clathrin endocytic pathway in viral infection
EMBO J.
(1998)
A. Benmerah et al.
AP-2/Eps15 interaction is required for receptor-mediated endocytosis
J. Cell Biol.
(1998)

R. Carbone et al.

eps15 and eps15R are essential components of the endocytic pathway

Cancer Res.

(1997)

S. van Delft et al.

Association and colocalization of Eps15 with adaptor protein-2 and clathrin

J. Cell Biol.

(1997)

J. Barbosa et al.

Trafficking of the vesicular acetylcholine transporter in SN56 cells: a dynamin-sensitive step and interaction with the AP-2 adaptor complex

J. Neurochem.

(2002)

V.I. Slepnev et al.

Tandem arrangement of the clathrin and AP-2 binding domains in amphiphysin 1 and disruption of clathrin coat function by amphiphysin fragments comprising these sites

J. Biol. Chem.

(2000)

C.M. Crump et al.

Phosphorylation of the medium chain subunit of the AP-2 adaptor complex does not influence its interaction with the tyrosine based internalisation motif of TGN38

FEBS Lett.

(1999)

J.E. Hinshaw et al.

Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding

Nature

(1995)

C. Bucci et al.

The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway

Cell

(1992)

J.P. Gorvel et al.

rab5 controls early endosome fusion in vitro

Cell

(1991)

K. Lindmo et al.

Regulation of membrane traffic by phosphoinositide 3-kinases

J. Cell Sci.

(2006)

A.T. Jones et al.

Phosphatidylinositol 3-kinase activity is required for early endosome fusion

Biochem. J.

(1995)

G. Li et al.

Evidence for phosphatidylinositol 3-kinase as a regulator of endocytosis via activation of Rab5

Proc. Natl. Acad. Sci. U.S.A.

(1995)

E.J. Smart et al.

Caveolins, liquid-ordered domains, and signal transduction

Mol. Cell Biol.

(1999)

A.W. Cohen et al.

Role of caveolae and caveolins in health and disease

Physiol. Rev.

(2004)

S. Matveev et al.

The role of caveolae and caveolin in vesicle-dependent and vesicle-independent trafficking

Adv. Drug Deliv. Rev.

(2001)

R.G. Anderson

The caveolae membrane system

Annu. Rev. Biochem.

(1998)

L. Pelkmans et al.

Endocytosis via caveolae

Traffic

(2002)

J.E. Schnitzer

Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo

Adv. Drug Deliv. Rev.

(2001)

I.R. Nabi et al.

Caveolae/raft-dependent endocytosis

J. Cell Biol.

(2003)

B. Razani et al.

Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae

Mol. Cell Biol.

(2002)

M. Drab et al.

Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice

Science

(2001)

F. Galbiati et al.

Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin–glycoprotein complex, and T-tubule abnormalities

J. Biol. Chem.

(2001)

M.P. Lisanti et al.

Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease

J. Cell Biol.

(1994)

T. Okamoto et al.

Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane

J. Biol. Chem.

(1998)

F. Galbiati et al.

Emerging themes in lipid rafts and caveolae

Cell

(2001)

J. Couet et al.

Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins

J. Biol. Chem.

(1997)

L. Johannes et al.

Clathrin-dependent or not: is it still the question?

Traffic

(2002)

M. Felberbaum-Corti et al.

Sliding doors: clathrin-coated pits or caveolae?

Nat. Cell Biol.

(2003)

G.M. Di Guglielmo et al.

Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover

Nat. Cell Biol.

(2003)

P.S. McPherson et al.

Signaling on the endocytic pathway

Traffic

(2001)

V. Cavalli et al.

Endocytosis and signaling cascades: a close encounter

FEBS Lett.

(2001)

A. Sorkin et al.

Signal transduction and endocytosis: close encounters of many kinds

Nat. Rev. Mol. Cell Biol.

(2002)

G.M. Di Guglielmo et al.

Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma

EMBO J.

(1994)

L.K. Bobanovic et al.

P2X receptor trafficking in neurons is subunit specific

J. Neurosci.

(2002)

A. Wilde et al.

EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake

Cell

(1999)

M.F. Ware et al.

Overexpression of cellular Src in fibroblasts enhances endocytic internalization of epidermal growth factor receptor

J. Biol. Chem.

(1997)

M.L. Chen et al.

Unique biochemical and behavioral alterations in drosophilashibirets1 mutants imply a conformational state affecting dynamin subcellular distribution and synaptic vesicle cycling

J. Neurobiol.

(2002)

L. De Vries et al.

RGS-GAIP, a GTPase-activating protein for galpha i heterotrimeric G proteins, is located on clathrin-coated vesicles

Mol. Biol. Cell

(1998)

P.E. Stenberg et al.

The Src family kinases, Fgr, Fyn, Lck, and Lyn, colocalize with coated membranes in platelets

Blood

(1997)

A. Schlegel et al.

The caveolin triad: caveolae biogenesis, cholesterol trafficking, and signal transduction

Cytokine Growth Factor Rev.

(2001)

A. Stoddart et al.

Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization

Immunity

(2002)

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Regulation of sodium pump endocytosis by cardiotonic steroids: Molecular mechanisms and physiological implications

Abstract

Introduction

Section snippets

Mechanisms of endocytosis

Endocytosis and signal transduction

Na/K-ATPase: an ion pump and a signal transducer

Endocytosis of the Na/K-ATPase in the regulation of renal sodium excretion

Ouabain-induced endocytosis of the Na/K-ATPase in LLC-PK1 cells

Ouabain regulates sodium handling in renal proximal tubule

Ouabain-Na/K-ATPase in endocytic pathway: signaling termination or propagation?

Physiological implications

Acknowledgement

When cell biology meets development: endocytic regulation of signaling pathways

Genes Dev.

The effect of cytochalasin B and colchicine on concanavalin A induced vacuolation in mouse peritoneal macrophages

Exp. Cell Res.

Diacylglycerols and PMA are particularly effective stimulators of fluid pinocytosis in human neutrophils

J. Cell. Physiol.

Dynamin-dependent and dynamin-independent processes contribute to the regulation of single vesicle release kinetics and quantal size

Proc. Natl. Acad. Sci. U.S.A.

Coat proteins: shaping membrane transport

Nat. Rev. Mol. Cell Biol.

Three ways to make a vesicle

Nat. Rev. Mol. Cell Biol.

Biological basket weaving: formation and function of clathrin-coated vesicles

Annu. Rev. Cell Dev. Biol.

Sequential steps in clathrin-mediated synaptic vesicle endocytosis

Curr. Opin. Neurobiol.

The clathrin endocytic pathway in viral infection

EMBO J.

AP-2/Eps15 interaction is required for receptor-mediated endocytosis

J. Cell Biol.

eps15 and eps15R are essential components of the endocytic pathway

Cancer Res.

Association and colocalization of Eps15 with adaptor protein-2 and clathrin

J. Cell Biol.

Trafficking of the vesicular acetylcholine transporter in SN56 cells: a dynamin-sensitive step and interaction with the AP-2 adaptor complex

J. Neurochem.

Tandem arrangement of the clathrin and AP-2 binding domains in amphiphysin 1 and disruption of clathrin coat function by amphiphysin fragments comprising these sites

J. Biol. Chem.

Phosphorylation of the medium chain subunit of the AP-2 adaptor complex does not influence its interaction with the tyrosine based internalisation motif of TGN38

FEBS Lett.

Dynamin self-assembles into rings suggesting a mechanism for coated vesicle budding

Nature

The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway

Cell

rab5 controls early endosome fusion in vitro

Cell

Regulation of membrane traffic by phosphoinositide 3-kinases

J. Cell Sci.

Phosphatidylinositol 3-kinase activity is required for early endosome fusion

Biochem. J.

Evidence for phosphatidylinositol 3-kinase as a regulator of endocytosis via activation of Rab5

Proc. Natl. Acad. Sci. U.S.A.

Caveolins, liquid-ordered domains, and signal transduction

Mol. Cell Biol.

Role of caveolae and caveolins in health and disease

Physiol. Rev.

The role of caveolae and caveolin in vesicle-dependent and vesicle-independent trafficking

Adv. Drug Deliv. Rev.

The caveolae membrane system

Annu. Rev. Biochem.

Endocytosis via caveolae

Traffic

Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo

Adv. Drug Deliv. Rev.

Caveolae/raft-dependent endocytosis

J. Cell Biol.

Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae

Mol. Cell Biol.

Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice

Science

Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin–glycoprotein complex, and T-tubule abnormalities

J. Biol. Chem.

Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease

J. Cell Biol.

Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane

J. Biol. Chem.

Emerging themes in lipid rafts and caveolae