title: Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period.
abstract: During pregnancy, the maternal endocrine pancreas undergoes, as a consequence of placental lactogens and prolactin (PRL) action, functional changes that are characterized by increased glucose-induced insulin secretion. After delivery, the maternal endocrine pancreas rapidly returns to non-pregnant state, which is mainly attributed to the increased serum levels of glucocorticoids (GCs). Although GCs are known to decrease insulin secretion and counteract PRL action, the mechanisms for these effects are poorly understood. We have previously demonstrated that signal transducer and activator of transcription 3 (STAT3) is increased in islets treated with PRL. In the present study, we show that STAT3 expression and serine phosphorylation are increased in pancreatic islets at the end of pregnancy (P19). STAT3 serine phosphorylation rapidly returned to basal levels 3 days after delivery (L3). The expression of the sarcoendoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2), a crucial protein involved in the regulation of calcium handling in beta-cells, was also increased in P19, returning to basal levels at L3. PRL increased SERCA2 and STAT3 expressions and STAT3 serine phosphorylation in RINm5F cells. The upregulation of SERCA2 by PRL was abolished after STAT3 knockdown. Moreover, PRL-induced STAT3 serine phosphorylation and SERCA2 expression were inhibited by dexamethasone (DEX). Insulin secretion from islets of P19 rats pre-incubated with thapsigargin and L3 rats showed a dramatic suppression of first phase of insulin release. The present results indicate that PRL regulates SERCA2 expression by a STAT3-dependent mechanism. PRL effect is counteracted by DEX and might contribute to the adaptation of maternal endocrine pancreas during the peripartum period.
authors.affiliation: Laboratory of Molecular Biology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Lineu Prestes Avenue 1524, São Paulo 05508-900, Brazil.
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhê
authors.forename: Tatiane C A
authors.initials: TC
authors.lastname: Nogueira
authors.forename: José E
authors.initials: JE
authors.lastname: Nicoletti-Carvalho
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Helena C
authors.initials: HC
authors.lastname: Barbosa
authors.forename: José
authors.initials: J
authors.lastname: Cipolla-Neto
authors.forename: José R
authors.initials: JR
authors.lastname: Bosqueiro
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D007328:Insulin / Q000032:analysis / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism*; D007774:Lactation / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011247:Pregnancy; D011388:Prolactin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection / Q000379:methods
chemical_list: C506948:Atp2a2 protein, rat; C506951:Atp2a3 protein, rat; D005938:Glucocorticoids; D007328:Insulin; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D003907:Dexamethasone; D011388:Prolactin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases