M. Diener et F. Hug, MODULATION OF CL- SECRETION IN RAT DISTAL COLON BY GENISTEIN, A PROTEIN-TYROSINE KINASE INHIBITOR, European journal of pharmacology, 299(1-3), 1996, pp. 161-170
The protein tyrosine kinase inhibitor, genistein, caused an increase o
f short-circuit current (Isc) across the rat distal colon in forskolin
-pretreated tissues, suggesting a synergistic interaction of the drug
with cAMP-dependent secretion. In the absence of forskolin, genistein
had a dual effect on Isc, it increased Isc in tissues with a low basel
ine, but decreased Isc in tissues with a high baseline Isc. The secret
ory effect of genistein was dependent on the presence of Cl- and was b
locked by inhibitors of Cl- secretion like bumetanide, an inhibitor of
the Na+-K+-Cl- cotransporter, or 5-nitro-2-(3-phenylpropylamino)-benz
oate (NPPB), a Cl- channel blocker. Unidirectional flux measurements r
evealed that genistein inhibited Na+ and Cl- absorption and induced ne
t Cl- secretion. The protein tyrosine phosphatase inhibitor vanadate s
uppressed the secretory effect of genistein. In contrast, genistein ca
used an inhibition of carbachol-induced, i.e. Ca2+-mediated secretion.
Whole-cell patch-clamp experiments confirmed the synergistic effect o
f genistein on cAMP-induced Cl- currents. In the presence of forskolin
, genistein caused a depolarization concomitant with an increase in me
mbrane inward current. In addition, genistein caused an inhibition of
a basal K+ conductance and inhibited the Ca2+-dependent K+ conductance
stimulated by carbachol. These results suggest a complex role of the
protein tyrosine kinase pathway in the control of colonic Cl- secretio
n, an antagonistic action on the cAMP pathway and a synergistic action
on the Ca2+ pathway as revealed by the opposing effects of genistein.
The physiological importance of this regulation remains to be clarifi
ed.