Progesterone modulates a neuronal nicotinic acetylcholine receptor.
The major brain nicotinic acetylcholine receptor is assembled from two subunits termed alpha 4 and n alpha 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.
Valera
S
S
Department of Biochemistry, Sciences II, Centre Medical Universitaire, Geneva, Switzerland.
Ballivet
M
M
Bertrand
D
D
D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000502:physiology*; D002784:Cholesterol / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials; D009865:Oocytes; D017354:Point Mutation; D011374:Progesterone / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000494:pharmacology; D014982:Xenopus laevis
D011978:Receptors, Nicotinic; D013739:Testosterone; D011374:Progesterone; D002784:Cholesterol; D000109:Acetylcholine