RT Journal Article
SR Electronic
T1 Pituitary Adenylate Cyclase-Activating Polypeptide Stimulates Secretoneurin Release and Secretogranin II Gene Transcription in Bovine Adrenochromaffin Cells through Multiple Signaling Pathways and Increased Binding of Pre-Existing Activator Protein-1-Like Transcription Factors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 42
OP 52
DO 10.1124/mol.60.1.42
VO 60
IS 1
A1 Valerie Turquier
A1 Laurent Yon
A1 Luca Grumolato
A1 David Alexandre
A1 Alain Fournier
A1 Hubert Vaudry
A1 Youssef Anouar
YR 2001
UL http://molpharm.aspetjournals.org/content/60/1/42.abstract
AB Secretoneurin (SN) is a novel bioactive peptide that derives from the neuroendocrine protein secretogranin II (SgII) by proteolytic processing and participates in neuro-immune communication. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP-38) dose-dependently stimulates (EC50 ∼ 3 nM) SN release (up to 4-fold) and SgII gene expression (up to 60-fold) in cultured bovine adrenochromaffin cells. The effect of PACAP on both SN secretion and SgII mRNA levels is rapid and long lasting. We analyzed in this neuroendocrine cell model the transduction pathways involved in both SN secretion and SgII gene transcription in response to PACAP. The cytosolic calcium chelator BAPTA-AM and the nonselective calcium channel antagonist NiCl2 equally inhibited both secretion of the peptide and transcription of the SgII gene, indicating a major contribution of calcium influx in PACAP-induced SN biosynthesis and release in chromaffin cells. Inhibition of protein kinase A (PKA) or C (PKC) also reduced PACAP-evoked SN release but did not alter the stimulatory effect of PACAP on SgII mRNA levels. Conversely, application of mitogen-activated protein kinase inhibitors suppressed PACAP-induced SgII gene expression. The effect of PACAP on SgII mRNA levels, like the effect of the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate (TPA), was not affected by cycloheximide, whereas the effects of the PKA stimulator forskolin or cell-depolarization by high K+ were significantly reduced by the protein synthesis inhibitor. PACAP and TPA both increased the binding activity of the SgII cAMP response element to trans-acting factors present in chromaffin cell nuclear extracts, which are recognized by antibodies to activator protein-1-related proteins. These data indicate that SN biosynthesis is regulated by PACAP in chromaffin cells through complex signaling cascades, suggesting that SN may play a function duringtrans-synaptic stimulation of the adrenal medulla. SNsecretoneurinSgIIsecretogranin IICgAchromogranin APACAPpituitary adenylate cyclase-activating polypeptidePAC1-Rpituitary adenylate cyclase-activating polypeptide-preferring receptorVIPvasoactive intestinal polypeptideMAPKmitogen-activated protein kinasePKCprotein kinase CPKAprotein kinase AAP-1activator protein-1TPA12-O-tetradecanoylphorbol 13-acetateBAPTA1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acidAMacetoxymethyl esterRIAradioimmunoassayERKextracellular signal-regulated kinaseEMSAelectrophoretic mobility shift assayVOCCsvoltage-operated calcium channelsATFactivating transcription factorsCREcAMP response elementCREBcAMP response element binding protein