Regulation of Na/H exchanger activity in glial tumor cells

L. A. McLean, N. K. Jorgensen, Peter M Cala

Research output: Contribution to journalArticle

Abstract

Glial tumor cells maintain a more alkaline intracellular pH (pHi) compared to non-transformed glial cells, despite increased H+ production. This increased pHi must therefore reflect differences in pH regulatory mechanisms between the tumor and normal glial cells, which may be exploited in order to control tumor growth. The steady-state pHi (in HCO3-free media) of the tumor cells ranged from 7.3 to 7.5, significantly (p<0.001) higher than that of the control astrocytes (pHi=7.0). A key pH regulatory mechanism is the Na/H exchanger (NHE), particularly in acidic medium when HCO3 is low. NHE activity following intracellular acidification (using NH4 prepulse) showed that maximum H+ flux during recovery was a linear function of 1/pHi. At any given pHi, the flux rate for the tumor cells was at least twice that for the control cells. Recovery from the acid load was dependent on extracellular Na and could be dose-dependently blocked by Amiloride and HOE694, inhibitors of the NHE. Calyculin A, a phosphatase inhibitor, caused a marked increase in pHi, which could be inhibited by Amiloride and HOE694. Calyculin also appeared to in duce altered phosphorylation of the exchanger, detected as a shift of protein banding on Western Blots. In addition to its role in pH regulation, the NHE is also involved in volume regulation in glial cells. Hyperosmotic cell shrinkage resulted in NHE activation, indicated by an increased pHi, which could be inhibited by Amiloride and HOE694. Based on these data, we propose that the glial tumor cells exhibit a higher pHi set point due to differences in isoforms of the NHE or modifications of the NHE regulatory pathway, such as different states of phosphorylation.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number3
StatePublished - 1997

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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