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Vol. 59, Issue 1, 16-23, January 2001
Department of Physiology & Cell Biology, University of
Nevada School of Medicine, Reno, Nevada
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites
of cytochrome P450 monooxygenase, which are released from endothelial
cells and dilate arteries. Dilation seems to be caused by activation of
large-conductance Ca2+-activated K+ channels
(BKCa) leading to membrane hyperpolarization. Previous studies suggest that EETs activate BKCa channels via
ADP-ribosylation of the G protein G
s with a subsequent
membrane-delimited action on the channel [Circ Res
78:415-423, 1996; 80:877-884, 1997;
85:349-356, 1999]. The present study examined whether this
pathway is present in human embryonic kidney (HEK) 293 cells when the
BKCa -subunit (cslo-) is
expressed without the 
-subunit. 11,12-EET increased outward
K+ current in whole-cell recordings of HEK293
cells. In cell-attached patches, 11,12-EET also increased the activity
of cslo- channels without affecting unitary conductance.
This action was mimicked by cholera toxin. The ADP-ribosyltransferase
inhibitors 3-aminobenzamide and m-iodobenxylguanidine
blocked the stimulatory effect of 11,12-EET. In inside-out patches
11,12-EET was without effect on channel activity unless GTP was
included in the bathing solution. GTP and GTP
S alone also activated
cslo- channels. Dialysis of cells with anti-Gs
antibody completely blocked the activation of cslo- channels by 11,12-EET, whereas anti-Gi/o and anti-G antibodies were without effect. The protein kinase A inhibitor KT5720 and the
adenylate cyclase inhibitor SQ22536 did not reduce the stimulatory effect of 11,12-EET on cslo- channels in cell-attached
patches. These data suggest that EET leads to Gs-dependent
activation of the cslo- subunits expressed in HEK293
cells and that the cslo- subunit is not required.
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