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Regulation of Uterine -Aminobutyric Acid_A Receptor Subunit Expression throughout Pregnancy¹

Department of Obstetrics, Gynecology, and Reproductive Sciences (E.F., S.H.M.), Center for Reproductive Sciences (E.F., S.H.M.), and Metabolic Research Unit (S.H.M.), University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Synthia H. Mellon, Ph.D., Department of Obstetrics and Gynecology, University of California, Box 0556, San Francisco, California 94143-0556. E-mail: mellon{at}cgl.ucsf.edu

Uterine contractions at parturition depend upon a variety of factors, including -aminobutyric acid (GABA)-ergic stimulation. A new subunit of the GABA_A receptor, , has recently been identified as being particularly abundant in the rat uterus. Reduced derivatives of progesterone, such as the 3,5-reduced derivative termed allopregnanolone, modulate GABA_A receptor activity and neuronal inhibition by modulating the frequency and duration of GABA_A channel opening. This modulation depends on the specific subunit composition of the GABA_A receptor. In particular, assembly of recombinant and GABA_A receptor subunits into a functional GABA_A receptor have been reported to reduce sensitivity to allopregnanolone. As allopregnanolone works through the GABA_A receptor to reduce uterine contraction, we hypothesized that incorporation of the -subunit into this receptor in the uterus might change the sensitivity of the GABA_A receptor to allopregnanolone and modulate parturition. We therefore determined the expression of GABA_A receptor subunit messenger RNAs (mRNAs) in rat uteri from various gestational ages and determined the physiological properties of the receptors. GABA_A -subunit mRNA abundance was constant throughout gestation, but decreased at the onset of labor. Other GABA_A subunits fluctuated differently during pregnancy: GABA_{A 1}-subunit mRNA expression increased, whereas ₂- and -subunit mRNA expression decreased during pregnancy, and ß₃-subunit mRNA only appeared on postpartum day 1. We determined how allopregnanolone affected the binding of muscimol, a ligand for the GABA_A receptor, to rat uterine GABA_A receptors throughout pregnancy. Allopregnanolone caused the greatest increase in muscimol binding to uterine GABA_A receptors at 19.5 days gestation and the least increase during labor, a time when and ₁ receptor subunit mRNA concentrations were low, and and ₂ receptor subunit mRNA concentrations were high. Thus, the subunit composition of the GABA_A receptor differs in rat uteri throughout gestation. These changes may also affect the sensitivity of the GABA_A receptor to allopregnanolone and thus contribute to the regulation of parturition.

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