The Cdc42 inhibitor secramine B prevents cAMP-induced K+ conductance in intestinal epithelial cells.
Biochem Pharmacol
; 71(12): 1720-6, 2006 Jun 14.
Article
em En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Potássio
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Benzazepinas
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AMP Cíclico
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Proteína cdc42 de Ligação ao GTP
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Mucosa Intestinal
Limite:
Humans
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article