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Vol. 58, Issue 2, 341-351, August 2000
4
2 Receptors
Expressed in HEK 293 Cells1
Departments of Anesthesiology (K.P., K.S., A.S.E., J.H.S.),
Psychiatry (C.F.Z.), and Molecular Biology and Pharmacology (D.F.C.),
Washington University School of Medicine, St. Louis, Missouri
Steroids, in addition to regulating gene expression, directly affect a
variety of ion channels. We examined the action of steroids on human
embryonic kidney 293 cells stably transfected to express rat 
4
2
neuronal nicotinic receptors. Each steroid that was tested inhibited
acetylcholine responses from these receptors, with slow kinetics
requiring seconds for block to develop and recover. The action of one
steroid [3,5,17-3-hydroxyandrostane-17-carbonitrile (ACN)]
was studied in detail. Block showed enantioselectivity, with an
IC50 value of 1.5 µM for ACN and 4.5 µM for the
enantiomer. Inhibition curves had Hill slopes larger than 1, indicating
more than one binding site per receptor. Block did not require
intracellular compounds containing high-energy phosphate bonds and was
not affected by analogs of GTP, suggesting that the mechanism does not
require the activation of second messengers. Block did not appear to be strongly selective between open and closed channel states or to involve
changes in desensitization. A comparison of different steroids showed
that a -orientation of groups at the 17 position produced more block
than -orientated diastereomers. The stereochemistry at the 3 and 5 positions was less influential for block of 42 nicotinic
receptors, despite its importance for potentiation of 
-aminobutyric
acidA receptors. The ability of steroids to block neuronal
nicotinic receptors correlated with their ability to produce anesthesia
in Xenopus tadpoles, but the concentrations required for
inhibition are generally greater. Similarly, the concentrations of
endogenous neurosteroids required to inhibit receptors are larger than
estimates of brain concentrations.
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