Critical role of protein kinase C alpha and calcium in growth factor induced activation of the Na(+)/H(+) exchanger NHE1

FEBS Lett. 2002 Jun 19;521(1-3):205-10. doi: 10.1016/s0014-5793(02)02867-3.


The ubiquitously expressed Na(+)/H(+) exchanger (NHE1) plays an important role in the regulation of the intracellular pH. Induction of NHE activity by phorbol esters and inhibition of growth factor-mediated stimulation of the NHE by protein kinase C (PKC) inhibitors suggest an implication of PKCs in the regulation of the NHE. Expression of PKC isotype-specific dominant negative and constitutively active mutants or downregulation of PKC by isotype-specific antisense oligonucleotides revealed that stimulation by epidermal growth factor (EGF) or phorbol ester of the NHE in NIH3T3 cells is a PKC(alpha)-specific effect. Elevation of cytoplasmic calcium by a Ca(2+) ionophore or thapsigargin causes a growth factor-independent stimulation of the NHE predominantly mediated by calcium/calmodulin kinase II. It is concluded that in NIH3T3 cells overexpressing the EGF receptor (EGFR6 cells), EGF requires cPKC(alpha) for the activation of the NHE, while calcium/calmodulin-dependent kinases are essential in thapsigargin induced stimulation of the NHE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcium / metabolism
  • Calcium / physiology*
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / metabolism*
  • Epidermal Growth Factor / pharmacology
  • Isoenzymes / biosynthesis
  • Isoenzymes / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Kinase C / biosynthesis
  • Protein Kinase C / physiology*
  • Protein Kinase C-alpha
  • Protein Kinase C-delta
  • Protein Kinase C-epsilon
  • Sodium-Hydrogen Exchangers / biosynthesis
  • Sodium-Hydrogen Exchangers / metabolism*
  • Thapsigargin / pharmacology


  • Enzyme Inhibitors
  • Isoenzymes
  • Sodium-Hydrogen Exchangers
  • growth factor-activatable Na-H exchanger NHE-1
  • Epidermal Growth Factor
  • Thapsigargin
  • Prkcd protein, mouse
  • Prkce protein, mouse
  • protein kinase C zeta
  • Prkca protein, mouse
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Protein Kinase C-delta
  • Protein Kinase C-epsilon
  • Mitogen-Activated Protein Kinases
  • Calcium