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C-peptide stimulates Na+,K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells

Zhong, Z. ; Kotova, O. LU ; Davidescu, A. ; Ehrén, I. ; Ekberg, K. ; Jörnvall, H. ; Wahren, J. and Chibalin, A. V. (2004) In Cellular and Molecular Life Sciences 61(21). p.2782-2790
Abstract

Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na+, K+-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na+,K +-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37°C for 10 min stimulated 86Rb+ uptake by 40% (p<0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive 86Rb+ uptake, C-peptide increased α subunit phosphorylation and basolateral membrane (BLM) abundance of the Na+,K+-ATPase α1 and... (More)

Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na+, K+-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na+,K +-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37°C for 10 min stimulated 86Rb+ uptake by 40% (p<0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive 86Rb+ uptake, C-peptide increased α subunit phosphorylation and basolateral membrane (BLM) abundance of the Na+,K+-ATPase α1 and β1 subunits. The increase in BLM abundance of the Na +,K+-ATPase α1 and β1 subunits was accompanied by depletion of α1 and β1 subunits from the endosomal compartments. C-peptide action on Na+,K+-ATPase was ERK1/2-dependent in HRTCs. C-peptide-stimulated Na+,K+-ATPase activation, phosphorylation of α1-subunit and translocation of α1 and β1 subunits to the BLM were abolished by a MEK1/2 inhibitor (20 μM PD98059). C-peptide stimulation of 86Rb+ uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 μM GF109203X). C-peptide stimulated phosphorylation of human Na+,K+-ATPase α subunit on Thr-Pro amino acid motifs, which form specific ERK substrates. In conclusion, C-peptide stimulates sodium pump activity via ERK1/2-induced phosphorylation of Thr residues on the α subunit of Na+,K+-ATPase.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
C-peptide, Kidney, MAP kinase, Na pump, PKC, Sodium pump
in
Cellular and Molecular Life Sciences
volume
61
issue
21
pages
2782 - 2790
publisher
Birkhäuser Verlag
external identifiers
  • pmid:15549182
  • scopus:11144264571
ISSN
1420-682X
DOI
10.1007/s00018-004-4258-x
language
English
LU publication?
no
id
f16652ee-188d-467f-b85b-4295e4bb1b61
date added to LUP
2019-06-03 13:29:23
date last changed
2020-05-26 05:23:03
@article{f16652ee-188d-467f-b85b-4295e4bb1b61,
  abstract     = {<p>Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na<sup>+</sup>, K<sup>+</sup>-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na<sup>+</sup>,K <sup>+</sup>-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37°C for 10 min stimulated <sup>86</sup>Rb<sup>+</sup> uptake by 40% (p&lt;0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive <sup>86</sup>Rb<sup>+</sup> uptake, C-peptide increased α subunit phosphorylation and basolateral membrane (BLM) abundance of the Na<sup>+</sup>,K<sup>+</sup>-ATPase α<sub>1</sub> and β<sub>1</sub> subunits. The increase in BLM abundance of the Na <sup>+</sup>,K<sup>+</sup>-ATPase α<sub>1</sub> and β<sub>1</sub> subunits was accompanied by depletion of α<sub>1</sub> and β<sub>1</sub> subunits from the endosomal compartments. C-peptide action on Na<sup>+</sup>,K<sup>+</sup>-ATPase was ERK1/2-dependent in HRTCs. C-peptide-stimulated Na<sup>+</sup>,K<sup>+</sup>-ATPase activation, phosphorylation of α<sub>1</sub>-subunit and translocation of α<sub>1</sub> and β<sub>1</sub> subunits to the BLM were abolished by a MEK1/2 inhibitor (20 μM PD98059). C-peptide stimulation of <sup>86</sup>Rb<sup>+</sup> uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 μM GF109203X). C-peptide stimulated phosphorylation of human Na<sup>+</sup>,K<sup>+</sup>-ATPase α subunit on Thr-Pro amino acid motifs, which form specific ERK substrates. In conclusion, C-peptide stimulates sodium pump activity via ERK1/2-induced phosphorylation of Thr residues on the α subunit of Na<sup>+</sup>,K<sup>+</sup>-ATPase.</p>},
  author       = {Zhong, Z. and Kotova, O. and Davidescu, A. and Ehrén, I. and Ekberg, K. and Jörnvall, H. and Wahren, J. and Chibalin, A. V.},
  issn         = {1420-682X},
  language     = {eng},
  month        = {11},
  number       = {21},
  pages        = {2782--2790},
  publisher    = {Birkhäuser Verlag},
  series       = {Cellular and Molecular Life Sciences},
  title        = {C-peptide stimulates Na<sup>+</sup>,K<sup>+</sup>-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells},
  url          = {http://dx.doi.org/10.1007/s00018-004-4258-x},
  doi          = {10.1007/s00018-004-4258-x},
  volume       = {61},
  year         = {2004},
}