Regulation of uterine gamma-aminobutyric acid(A) receptor subunit expression throughout pregnancy

Abstract

Uterine contractions at parturition depend upon a variety of factors, including gamma-aminobutyric acid (GABA)-ergic stimulation. A new subunit of the GABA(A) receptor, pi, has recently been identified as being particularly abundant in the rat uterus. Reduced derivatives of progesterone, such as the 3alpha,5alpha-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 pi and delta 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 pi-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) pi-subunit mRNA abundance was constant throughout gestation, but decreased at the onset of labor. Other GABA(A) subunits fluctuated differently during pregnancy: GABA(A) alpha(1)-subunit mRNA expression increased, whereas alpha(2)- and delta-subunit mRNA expression decreased during pregnancy, and beta(3)-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 pi and alpha(1) receptor subunit mRNA concentrations were low, and delta and alpha(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.