Progesterone-metabolite prevents protein kinase C-dependent modulation of gamma -aminobutyric acid type A receptors in oxytocin neurons

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Abstract
Gonadal steroid feedback to oxytocin neurons during pregnancy is in part mediated via the neurosteroid allopregnanolone (3α-OH-DHP), acting as allosteric modulator of postsynaptic γ-aminobutyric acid type A (GABAA) receptors. We describe here a form of nongenomic progesterone signaling by showing that 3α-OH-DHP not only potentiates GABAA receptor-channel activity but also prevents its modulation by protein kinase C (PKC). Application of oxytocin or stimulation of PKC suppressed the postsynaptic GABA responses of oxytocin neurons in the absence, but not in the presence of 3α-OH-DHP. This finding was true at the juvenile stage and during late pregnancy, when the GABAA receptor is sensitive to 3α-OH-DHP. In contrast, after parturition, when the GABAA receptors expressed by oxytocin neurons are less sensitive to 3α-OH-DHP, this neurosteroid no longer counteracts PKC. The change in GABAA-receptor responsiveness to 3α-OH-DHP helps to explain the onset of firing activity and thus the induction of oxytocin release at parturition.