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The Journal of Neuroscience, September 1, 2001, 21(17):6561-6568
The C Terminus of the Human Nicotinic  4 2 Receptor
Forms a Binding Site Required for Potentiation by an Estrogenic
Steroid
Ken
Paradiso,
Jessie
Zhang, and
Joe Henry
Steinbach
Department of Anesthesiology, Washington University School of
Medicine, St. Louis, Missouri 63110
In addition to actions mediated by changes in gene expression,
steroids can directly modulate several transmitter-gated and voltage-gated ion channels. Despite numerous studies showing that steroids enhance or reduce ion channel activity, the site(s) that mediates steroid recognition is not known. To identify the regions in
which steroids bind and affect ion channel activity, we have taken
advantage of the observation that human  4 2 neuronal nicotinic receptors are potentiated by an estrogen steroid, 17-estradiol, whereas a rat 42 receptor is not. Mutations indicate that a sequence (AGMI) at the end of the C terminus of the human 4 subunit forms a binding site required for 17-estradiol potentiation. In
contrast, ethynyl -estradiol (an oral contraceptive) potentiates both human and rat 42 receptors. A single tryptophan in the C
terminus of both the rat and the human 4 subunit is sufficient for
potentiation by ethynyl -estradiol, probably through a  - interaction. Mutation of this tryptophan eliminates the ability of
ethynyl -estradiol to potentiate rat receptors. However, in human
receptors it was necessary to mutate both the AGMI sequence and the
tryptophan to eliminate potentiation by ethynyl -estradiol. The
findings that -estradiol requires the AGMI sequence but that a
single C-terminal tryptophan is sufficient for potentiation by ethynyl
-estradiol indicate that the C terminus forms a binding site for
these steroids. The binding site(s) for block appears to differ from
those involved in potentiation because the C-terminal sequence does not
affect block by steroids such as progesterone, and progesterone does
not competitively inhibit potentiation.
Key words:
nicotinic receptors; estrogen; steroids; potentiation; binding site; ligand-gated ion channel
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176561-08$05.00/0
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