Referenced in: none

Automatically associated channels: Kv7.1

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

Authors: Henry E Pelish, William Ciesla, Nori Tanaka, Krishna Reddy, Matthew D Shair, Tomas Kirchhausen, Wayne I Lencer

Journal, date & volume: Biochem. Pharmacol., 2006 Jun 14 , 71, 1720-6

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16677615

Abstract
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.