Oxytocin regulates neurosteroid modulation of GABA(A) receptors in supraoptic nucleus around parturition.
In this study, we investigate how neurosteroid sensitivity of GABA(A) receptors (GABA(A)Rs) is regulated. We examined this issue in neurons of the supraoptic nucleus (SON) of the rat and found that, during parturition, the GABA(A)Rs become insensitive to the neurosteroid allopregnanolone attributable to a shift in the balance between the activities of endogenous Ser/Thr phosphatase and PKC. In particular, a constitutive endogenous tone of oxytocin within the SON after parturition suppressed neurosteroid sensitivity of GABA(A)Rs via activation of PKC. Vice versa before parturition, during late pregnancy, application of exogenous oxytocin brings the GABA(A)Rs from a neurosteroid-sensitive mode toward a condition in which the receptors are not sensitive. This indicates that there may be an inverse causal relationship between the extent to which the GABA(A)R or one of its interacting proteins is phosphorylated and the neurosteroid sensitivity of the GABA(A)R. Neurosteroid sensitivity was not affected by changes in subunit composition of GABA(A)Rs known to occur concurrently in these cells.
Koksma
Jan-Jurjen
JJ
Department of Experimental Neurophysiology, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
van Kesteren
Ronald E
RE
Rosahl
Thomas W
TW
Zwart
Ruud
R
Smit
August B
AB
Lüddens
Hartmut
H
Brussaard
Arjen B
AB
D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002460:Cell Line; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009865:Oocytes / Q000378:metabolism; D010121:Oxytocin / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011247:Pregnancy; D011280:Pregnanolone / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000494:pharmacology*; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D011963:Receptors, GABA-A; D013256:Steroids; D010121:Oxytocin; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases