α<sub>1</sub>-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter

Andersen, Geir Øystein; Skomedal, Tor; Enger, Mette; Fidjeland, Astrid; Brattelid, Trond; Levy, Finn Olav; Osnes, Jan-Bjørn

doi:10.1152/ajpheart.00549.2003

Cited by 23 publications

(16 citation statements)

References 30 publications

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“…Ventricular cardiomyocytes were isolated from adult rat hearts by enzymatic digestion with trypsin (60 U/mL) and collagenase (90 U/mL) as described by others 15 and mounted on glass slides for immunohistochemistry.…”

Section: Isolation Of Cardiomyocytes For Immunohistochemistrymentioning

confidence: 99%

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

et al. 2005

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Background-Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-B (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies. Methods and Results-Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction. Conclusions-These

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Section: Isolation Of Cardiomyocytes For Immunohistochemistrymentioning

confidence: 99%

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

et al. 2005

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“…Rat parotid NKCC1 is, in addition, phosphorylated by endogenous kinases associated with the basolateral plasma membrane and possibly coprecipitated with NKCC1 (19). Extracellular signal-regulated kinase (ERK) 1/2 kinases are implicated in the activation of cardiomyocyte NKCC by ␣ 1 -adrenergic agents (20) and human tracheal epithelial NKCC1 by hyperosmotic stress (21).…”

Section: Na-k-2cl Cotransporter (Nkcc1)mentioning

confidence: 99%

PKCδ Acts Upstream of SPAK in the Activation of NKCC1 by Hyperosmotic Stress in Human Airway Epithelial Cells

Smith

Smallwood

Liedtke

2008

Journal of Biological Chemistry

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“…ERK1/2 kinases are implicated in the activation of cardiomyocyte NKCC by ␣ 1 -adrenergic agents (12) and human tracheal epithelial NKCC1 by hyperosmotic stress (13).…”

Section: Namentioning

confidence: 99%

Role for Protein Phosphatase 2A in the Regulation of Calu-3 EpithelialNa+-K+-2Cl–, Type 1 Co-transportFunction

Liedtke

Wang

Smallwood

2005

Journal of Biological Chemistry

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Activity of Na؉ -K ؉ -2Cl ؊ co-transport (NKCC1) in epithelia is thought to be highly regulated through phosphorylation and dephosphorylation of the transporter. Previous functional studies from this laboratory suggested a role for protein phosphatase 2A (PP2A) as a serine/threonine protein phosphatase involved in the regulation of mammalian tracheal epithelial NKCC1. We expand on these studies to characterize serine/ threonine protein phosphatase(s) necessary for regulation of NKCC1 function and the interaction of the phosphatase(s) with proteins associated with NKCC1. NKCC1 activity was measured as bumetanide-sensitive 86 Rb uptake or basolateral to apical 86 Rb flux in primary cultures of human tracheal epithelial cells or in Calu-3 airway epithelial cells grown on Transwell filter inserts. Preincubation with 0.1 nM okadaic acid, a PP2A > > phosphatase 1 (PP1) inhibitor, increased NKCC1 activity 3.5-fold in human tracheal epithelial cells and 4.1-fold in Calu-3 cells. Calyculin, a PP1 > > PP2A inhibitor, did not alter NKCC1 activity or percent bumetanide-sensitive flux. The effect of OA was dose-dependent with an IC 50 of 0.4 nM. The ␣ 1 -adrenergic agonist methoxamine increased NKCC1 activity and transiently increased PP2A activity 3.8-fold but did not alter PP1 activity. OA augmented methoxaminedependent stimulation of NKCC1 activity. PP1, PP2A, and PP2C but not PP2B were detected in lysates from Calu-3 cells by immunoblot analysis. PP1 was not detected in immunoprecipitates of NKCC1 and vice versa. PP2A co-immunoprecipitated with NKCC1 and protein kinase C-␦ (PKC-␦) and was pulled down by a recombinant N terminus of NKCC1 consisting of amino acids 1-286. One novel finding is co-precipitation of STE20-related proline-alanine-rich kinase, a regulatory kinase for NKCC1, with PP2A and PKC-␦. The results suggest a model of actin serving as a scaffold for binding and association of PKC-␦, PP2A, and STE20-related proline-alanine-rich kinase. The role of the complex of serine/threonine protein kinases and a protein phosphatase is probably the maintenance of optimal phosphorylation of NKCC1 coincident with its physiological function in epithelial absorption and secretion.1 is a member of a large gene family of cation-Cl co-transporters, which are characterized by the coupled transport of Cl with K in the absence (KCC) or presence (NKCC1, NKCC2) of sodium (1). The cation-Cl co-transporters mediate a highly regulated influx of electrolytes in an electroneutral manner in epithelia and other cell types. In epithelia, NKCC isoforms participate in fluid and electrolyte secretion and absorption, depending on the localization of NKCC to basolateral or apical plasma membrane, respectively. In secretory epithelia, NKCC1 is oriented to translocate the ions sodium, potassium, and chloride from the blood into cells. These epithelia also typically express a Cl channel in the apical membrane. Stimulation of secretion results in the activation of NKCC1 and apical Cl channels, thus allowing movement of Cl from the blood into cells ...

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α₁-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter

Cited by 23 publications

References 30 publications

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

PKCδ Acts Upstream of SPAK in the Activation of NKCC1 by Hyperosmotic Stress in Human Airway Epithelial Cells

Role for Protein Phosphatase 2A in the Regulation of Calu-3 EpithelialNa+-K+-2Cl–, Type 1 Co-transportFunction

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α1-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter

Cited by 23 publications

References 30 publications

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

Dysregulated Osteoprotegerin/RANK Ligand/RANK Axis in Clinical and Experimental Heart Failure

PKCδ Acts Upstream of SPAK in the Activation of NKCC1 by Hyperosmotic Stress in Human Airway Epithelial Cells

Role for Protein Phosphatase 2A in the Regulation of Calu-3 EpithelialNa+-K+-2Cl–, Type 1 Co-transportFunction

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α₁-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter