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Vol. 55, Issue 2, 269-278, February 1999
Department of Neurobiology, Harvard Medical School, Boston,
Massachusetts
17,21-Dimethyl-19-nor-pregn-4,9-diene-3,20-dione (promegestone) was
used to characterize the mechanism of inhibition of nicotinic acetylcholine (ACh) receptors (AChR) by progestin steroids.
Promegestone reversibly inhibited ACh-induced currents of
Torpedo AChRs expressed in Xenopus
oocytes. Between 1-30 µM promegestone produced a
concentration-dependent enhancement of the equilibrium binding affinity
of [3H]ACh to Torpedo AChR-rich membranes.
For AChRs in the presence of agonist (desensitized state) promegestone
was a more potent inhibitor of the binding of the noncompetitive
antagonist [3H]phencyclidine (IC50 = 9 µM)
than of [3H]histrionicotoxin (IC50 ~ 100 µM). To identify AChR domains in contact with the steroid, AChR-rich
membranes equilibrated with [3H]promegestone were
irradiated at 312 nm, and 3H-labeled amino acids were
identified by amino-terminal sequencing of fragments isolated from
subunit proteolytic digests. Within AChR 
-subunit, 70% of
3H was covalently incorporated in a 10-kDa fragment
beginning at Asn-339 and containing the M4 membrane spanning segment,
and 30% was in a 20-kDa fragment beginning at Ser-173 and containing
the M1-M3 segments. Fragments containing the M2 channel domains as well as the M4 segments were isolated from proteolytic digests of AChR
subunits and subjected to amino-terminal sequence analysis. No evidence
of [3H]promegestone incorporation was detected in any of
the M2 segments. The amino acids in the M4 segments labeled by
[3H]promegestone were among those previously shown to be
in contact with the lipid bilayer (). These
results indicate that the steroid promegestone is an AChR
noncompetitive antagonist that may alter AChR function by interactions
at the lipid-protein interface.
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