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Research ArticleArticle

A Crucial Role for the Mitogen-Activated Protein Kinase Pathway in Nicotinic Cholinergic Signaling to Secretory Protein Transcription in Pheochromocytoma Cells

Kechun Tang, Hongjiang Wu, Sushil K. Mahata and Daniel T. O’Connor
Molecular Pharmacology July 1998, 54 (1) 59-69; DOI: https://doi.org/10.1124/mol.54.1.59
Kechun Tang
Department of Medicine and Center for Molecular Genetics, University of California, and Department of Veterans Affairs Medical Center, San Diego, California
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Hongjiang Wu
Department of Medicine and Center for Molecular Genetics, University of California, and Department of Veterans Affairs Medical Center, San Diego, California
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Sushil K. Mahata
Department of Medicine and Center for Molecular Genetics, University of California, and Department of Veterans Affairs Medical Center, San Diego, California
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Daniel T. O’Connor
Department of Medicine and Center for Molecular Genetics, University of California, and Department of Veterans Affairs Medical Center, San Diego, California
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Abstract

The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto the chromogranin A promoter proximal CRE. We therefore probed the role of the MAPK pathway in chromogranin A biosynthesis after secretory stimulation of PC12 pheochromocytoma cells by the nicotinic cholinergic pathway, the physiological secretory trigger. Chemical inhibition of either MAPK or MAPK kinase blocked the response of a transfected chromogranin A promoter to nicotine or protein kinase C activation [by phorbol-12-myristate-13-acetate (PMA)], although nicotine-evoked catecholamine secretion was unaffected. Activation of the MAP kinase cascade (Ras, Raf, MAPK, or CREB kinase) by cotransfection of pathway components stimulated the chromogranin A promoter. Cotransfection of MAPK pathway dominant negative mutants (for Raf, MAPK, or CREB kinase) blocked nicotinic or PMA activation of chromogranin A, although a dominant negative Ras mutant was without effect. MAPK pathway enzymatic activity was stimulated by both nicotine and PMA. Point mutations of the chromogranin A CRE suggested that this element was necessary incis for stimulation by nicotine, PMA, or chemical activation of the MAPK pathway. Transfer of the CRE to a heterologous promoter conferred inducibility by not only nicotine or cAMP but also MAPK activation. Expression of the CREB antagonist KCREB blocked the response of the chromogranin A promoter to nicotine, cAMP, or MAPK pathway activation by either chemical stimulation or cotransfection of active cascade components. Chromogranin A mRNA responded to MAPK pathway manipulation in a fashion similar to the transfected chromogranin A promoter, in both direction and magnitude. We conclude that the MAPK pathway is a necessary intermediate in signaling from the nicotinic receptor to secretory protein transcription, although not to catecholamine secretion. In trans, this response seems to involve the following signal cascade: protein kinase C → Raf → MAPK kinase → MAPK → CREB kinase → CREB. In cis, activation by the cascade maps onto the chromogranin A promoter proximal CRE, which is both necessary and sufficient to confer the response.

Footnotes

    • Received December 23, 1997.
    • Accepted March 18, 1998.
  • Send reprint requests to: Daniel T. O’Connor, MD, Department of Medicine and Center for Molecular Genetics (9111H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail: doconnor{at}ucsd.edu

  • This work was supported by the Department of Veterans Affairs, the National Institutes of Health, and the National Kidney Foundation.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

A Crucial Role for the Mitogen-Activated Protein Kinase Pathway in Nicotinic Cholinergic Signaling to Secretory Protein Transcription in Pheochromocytoma Cells

Kechun Tang, Hongjiang Wu, Sushil K. Mahata and Daniel T. O’Connor
Molecular Pharmacology July 1, 1998, 54 (1) 59-69; DOI: https://doi.org/10.1124/mol.54.1.59

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Research ArticleArticle

A Crucial Role for the Mitogen-Activated Protein Kinase Pathway in Nicotinic Cholinergic Signaling to Secretory Protein Transcription in Pheochromocytoma Cells

Kechun Tang, Hongjiang Wu, Sushil K. Mahata and Daniel T. O’Connor
Molecular Pharmacology July 1, 1998, 54 (1) 59-69; DOI: https://doi.org/10.1124/mol.54.1.59
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