title: Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin.
abstract: Pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) augment the biosynthesis of tyrosine hydroxylase (TH). We tested whether secretin belonging to the glucagon/PACAP/VIP superfamily would increase transcription of the tyrosine hydroxylase (Th) gene and modulate catecholamine secretion. Secretin activated transcription of the endogenous Th gene and its transfected promoter (EC(50) ∼4.6 nM) in pheochromocytoma (PC12) cells. This was abolished by pre-treatment with a secretin receptor (SCTR) antagonist and by inhibition of protein kinase A (PKA), mitogen-activated protein kinase, or CREB (cAMP response element-binding protein). In agreement, secretin increased PKA activity and induced phosphorylation of CREB and binding to Th CRE, suggesting secretin signaling to transcription via a PKA-CREB pathway. Secretin stimulated catecholamine secretion (EC(50) ∼3.5 μM) from PC12 cells, but this was inhibited by pre-treatment with VIP-preferring receptor (VPAC1)/PACAP-preferring receptor (PAC1) antagonists. Secretin-evoked secretion occurred without extracellular Ca(2+) and was abolished by intracellular Ca(2+) chelation. Secretin augmented phospholipase C (PLC) activity and increased inositol-1,4,5-triphosphate (IP(3)) levels in PC12 cells; PLC-β inhibition blocked secretin-induced catecholamine secretion, indicating the participation of intracellular Ca(2+) from a phospholipase pathway in secretion. Like PACAP, secretin evoked long-lasting catecholamine secretion, even after only a transient exposure. Thus, transcription is triggered by nanomolar concentrations of the peptide through SCTR, with signaling along the cAMP-PKA and extracellular-signal-regulated kinase 1/2 pathways and through CREB. By contrast, secretion is triggered only by micromolar concentrations of peptide through PAC1/VPAC receptors and by utilizing a PLC/intracellular Ca(2+) pathway.
authors: Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA.
authors: Manjula
authors: M
authors: Mahata
authors: Kuizing
authors: K
authors: Zhang
authors: Jiaur R
authors: JR
authors: Gayen
authors: Suvobroto
authors: S
authors: Nandi
authors: Bhawanjit K
authors: BK
authors: Brar
authors: Sajalendu
authors: S
authors: Ghosh
authors: Nitish R
authors: NR
authors: Mahapatra
authors: Laurent
authors: L
authors: Taupenot
authors: Daniel T
authors: DT
authors: O'Connor
authors: Sushil K
authors: SK
authors: Mahata
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