The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells

Biochem Pharmacol. 2006 Jun 14;71(12):1720-6. doi: 10.1016/j.bcp.2006.03.011. Epub 2006 Mar 18.


Cyclic AMP- (cAMP) and calcium-dependent agonists stimulate chloride secretion through the coordinated activation of distinct apical and basolateral membrane channels and ion transporters in mucosal epithelial cells. Defects in the regulation of Cl- transport across mucosal surfaces occur with cystic fibrosis and V. cholerae infection and can be life threatening. Here we report that secramine B, a small molecule that inhibits activation of the Rho GTPase Cdc42, reduced cAMP-stimulated chloride secretion in the human intestinal cell line T84. Secramine B interfered with a cAMP-gated and Ba2+-sensitive K+ channel, presumably KCNQ1/KCNE3. This channel is required to maintain the membrane potential that sustains chloride secretion. In contrast, secramine B did not affect the Ca2+-mediated chloride secretion pathway, which requires a separate K+ channel activity from that of cAMP. Pirl1, another small molecule structurally unrelated to secramine B that also inhibits Cdc42 activation in vitro, similarly inhibited cAMP-dependent but not Ca2+-dependent chloride secretion. These results suggest that Rho GTPases may be involved in the regulation of the chloride secretory response and identify secramine B an inhibitor of cAMP-dependent K+ conductance in intestinal epithelial cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Benzazepines / pharmacology*
  • Cell Line
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / pharmacology*
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Ion Channel Gating
  • Ion Transport
  • Potassium / metabolism*
  • cdc42 GTP-Binding Protein / antagonists & inhibitors*


  • Benzazepines
  • secramine B
  • Cyclic AMP
  • cdc42 GTP-Binding Protein
  • Potassium