| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Departments of Medicine and Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and 2 Magainin Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania 19642
Squalamine, an endogenous molecule found in the liver and other tissues of Squalus acanthias, has antibiotic properties and causes changes in endothelial cell shape. The latter suggested that its potential targets might include transport proteins that control cell volume or cell shape. The effect of purified squalamine was examined on cloned Na+/H+ exchanger isoforms NHE1, NHE2, and NHE3 stably transfected in PS120 fibroblasts. Squalamine (1-h pretreatment) decreased the maximal velocity of rabbit NHE3 in a concentration-dependent manner (13, 47, and 57% inhibition with 3, 5, and 7 µg/ml, respectively) and also increased K'[H+]i. Squalamine did not affect rabbit NHE1 or NHE2 function. The inhibitory effect of squalamine was 1) time dependent, with no effect of immediate addition and maximum effect with 1 h of exposure, and 2) fully reversible. Squalamine pretreatment of the ileum for 60 min inhibited brush-border membrane vesicle Na+/H+ activity by 51%. Further investigation into the mechanism of squalamine's effects showed that squalamine required the COOH-terminal 76 amino acids of NHE3. Squalamine had no cytotoxic effect at the concentrations studied, as indicated by monitoring lactate dehydrogenase release. These results indicate that squalamine 1) is a specific inhibitor of the brush-border NHE isoform NHE3 and not NHE1 or NHE2, 2) acts in a nontoxic and fully reversible manner, and 3) has a delayed effect, indicating that it may influence brush-border Na+/H+ exchanger function indirectly, through an intracellular signaling pathway or by acting as an intracellular modulator.
sodium absorption; intestinal brush border
This article has been cited by other articles:
|
|
 |
|
  M. Xiang, M. Feng, S. Muend, and R. Rao A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension PNAS, November 20, 2007; 104(47): 18677 - 18681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Donowitz and X. Li Regulatory Binding Partners and Complexes of NHE3 Physiol Rev, July 1, 2007; 87(3): 825 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Chernova, D. H. Vandorpe, J. S. Clark, J. I. Williams, M. A. Zasloff, L. Jiang, and S. L. Alper Apparent receptor-mediated activation of Ca2+-dependent conductive Cl- transport by shark-derived polyaminosterols Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1644 - R1658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K. Dy and A. A. Adjei Novel Targets for Lung Cancer Therapy: Part II J. Clin. Oncol., July 1, 2002; 20(13): 3016 - 3028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bhargava, J. L. Marshall, W. Dahut, N. Rizvi, N. Trocky, J. I. Williams, H. Hait, S. Song, K. J. Holroyd, and M. J. Hawkins A Phase I and Pharmacokinetic Study of Squalamine, a Novel Antiangiogenic Agent, in Patients with Advanced Cancers Clin. Cancer Res., December 1, 2001; 7(12): 3912 - 3919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Cavet, S. Akhter, F. S. de Medina, M. Donowitz, and C.-M. Tse Na+/H+ exchangers (NHE1-3) have similar turnover numbers but different percentages on the cell surface Am J Physiol Cell Physiol, December 1, 1999; 277(6): C1111 - C1121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Schiller and G. Bittner Potentiation of Platinum Antitumor Effects in Human Lung Tumor Xenografts by the Angiogenesis Inhibitor Squalamine: Effects on Tumor Neovascularization Clin. Cancer Res., December 1, 1999; 5(12): 4287 - 4294. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
