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Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin

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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 (EC50 ∼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 (EC50 ∼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 Ca2+ and was abolished by intracellular Ca2+ chelation. Secretin augmented phospholipase C (PLC) activity and increased inositol-1,4,5-triphosphate (IP3) levels in PC12 cells; PLC-β inhibition blocked secretin-induced catecholamine secretion, indicating the participation of intracellular Ca2+ 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 Ca2+ pathway.

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Abbreviations

Chga :

Chromogranin A gene

CRE:

cAMP response element

ERK:

Extracellular-signal-regulated kinase

GPCR:

G-protein-coupled receptor

IP3 :

Inositol-1,4,5-triphosphate

PAC1:

PACAP-preferring receptor

PACAP:

Pituitary adenylyl cyclase activating polypeptide

PHI:

Peptide histidine isoleucine

PKA:

Protein kinase A

PLC:

Phospholipase C

RT-PCR:

Reverse transcription followed by polymerase Chain reaction

SCTR:

Secretin receptor

Sctr :

Secretin receptor gene

TH:

Tyrosine hydroxylase enzyme

Th :

TH gene

VIP:

Vasoactive intestinal polypeptide

VPAC1:

VIP-preferring receptor

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Authors and Affiliations

  1. Department of Medicine, University of California, San Diego (0838), 9500 Gilman Drive, La Jolla, CA 92093–0838, USA

    Manjula Mahata, Kuizing Zhang, Suvobroto Nandi, Bhawanjit K. Brar, Laurent Taupenot, Daniel T. O’Connor & Sushil K. Mahata

  2. Division of Pharmakokinetics & Metabolism, Central Drug Research Institute, Lucknow, India

    Jiaur R. Gayen

  3. Department of Zoology, Postgraduate Department of Ranchi College, Ranchi, India

    Sajalendu Ghosh

  4. Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India

    Nitish R. Mahapatra

  5. VA San Diego Healthcare System, San Diego, Calif., USA

    Daniel T. O’Connor & Sushil K. Mahata

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  1. Manjula Mahata
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  2. Kuizing Zhang
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  3. Jiaur R. Gayen
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  8. Laurent Taupenot
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  10. Sushil K. Mahata
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Correspondence to Sushil K. Mahata.

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This work was supported by grants from the Department of Veterans Affairs (to S.K.M. and D.T.O’C.) and the National Institutes of Health (R01 DA011311 to S.K.M.).

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Mahata, M., Zhang, K., Gayen, J.R. et al. Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin. Cell Tissue Res 345, 87–102 (2011). https://doi.org/10.1007/s00441-011-1177-7

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