Regulation of Uterine  -Aminobutyric AcidA 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.

Deletion of the Mouse P450c17 Gene Causes Early Embryonic Lethality

“…Steroid synthesis in pregnancy involves the maternal ovarian corpus luteum, the placenta, and, in some species, the fetus as well. Progesterone is required to suppress uterine contractility and maintain pregnancy (20,29,38,40). In human beings, a luteal-placental shift occurs by the end of the first trimester, and the maternal ovary is no longer necessary after this time (42).…”

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

“…One study (Fujii & Mellon, 2001) examined the changes in GABAR subunits which accompany pregnancy: α1 expression increased and α2 and δ expression decreased, whereas expression of the ð subunit decreased at the onset of labor. These changes were accompanied by altered responsiveness to THP, with the greatest response on day 19 of pregnancy, when THP levels peak, and the least sensitive period at the onset of labor, when uterine contractility is maximal (Fujii & Mellon, 2001). …”

Neurosteroid regulation of central nervous system development

“…Changes in sensitivity of GABA A receptors toward allopregnanolone, due to alterations in subunit composition, are induced by neurosteroid withdrawal (Biggio et al, 2006;Gulinello et al, 2002;Mascia et al, 2002;Smith et al, 1998), long term steroid administration (Follesa et al, 2002) and in animal models of epilepsy (Banerjee et al, 1998;Brussaard and Herbison, 2000;Cagetti et al, 2003;Devaud et al, 1996;Follesa et al, 2000;Gulinello et al, 2002;Mtchedlishvili et al, 2001;Reddy and Rogawski, 2000), as well as to changes in neurosteroid concentrations resulting from pregnancy (Concas et al, 1998;Fujii and Mellon, 2001;Herbison, 2001), stress (Barbaccia et al, 1996), social isolation (Pinna et al, 2004;Serra et al, 2000), as well as due to age of the animal (Shen et al, 2007) …”