Progesterone-metabolite prevents protein kinase C-dependent modulation of gamma-aminobutyric acid type A receptors in oxytocin neurons.
Gonadal steroid feedback to oxytocin neurons during pregnancy is in part mediated via the neurosteroid allopregnanolone (3alpha-OH-DHP), acting as allosteric modulator of postsynaptic gamma-aminobutyric acid type A (GABA(A)) receptors. We describe here a form of nongenomic progesterone signaling by showing that 3alpha-OH-DHP not only potentiates GABA(A) 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 3alpha-OH-DHP. This finding was true at the juvenile stage and during late pregnancy, when the GABA(A) receptor is sensitive to 3alpha-OH-DHP. In contrast, after parturition, when the GABA(A) receptors expressed by oxytocin neurons are less sensitive to 3alpha-OH-DHP, this neurosteroid no longer counteracts PKC. The change in GABA(A)-receptor responsiveness to 3alpha-OH-DHP helps to explain the onset of firing activity and thus the induction of oxytocin release at parturition.
Brussaard
A B
AB
Department of Neurophysiology, Institute for Neurosciences, Vrije Universiteit Amsterdam, de Boelelaan 1087, 1081 HV, Amsterdam, The Netherlands. brssrd@bio.vu.nl
Wossink
J
J
Lodder
J C
JC
Kits
K S
KS
D000494:Allosteric Regulation; D000818:Animals; D005260:Female; D058785:GABA-A Receptor Agonists; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D009474:Neurons / Q000502:physiology*; D010121:Oxytocin / Q000502:physiology*; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D015398:Signal Transduction
D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D011374:Progesterone; D010121:Oxytocin; D011280:Pregnanolone; D011493:Protein Kinase C