title: The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells.
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.
authors: Department of Cell Biology and the CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, USA.
authors: Henry E
authors: HE
authors: Pelish
authors: William
authors: W
authors: Ciesla
authors: Nori
authors: N
authors: Tanaka
authors: Krishna
authors: K
authors: Reddy
authors: Matthew D
authors: MD
authors: Shair
authors: Tomas
authors: T
authors: Kirchhausen
authors: Wayne I
authors: WI
authors: Lencer