Serotonergic repression of mitogen-activated protein kinase control of the calcitonin gene-related peptide enhancer

Molecular Endocrinology
Paul L Durham, A F Russo

Abstract

We have investigated the mechanisms underlying regulation of the calcitonin gene-related peptide (CGRP) cell-specific enhancer. Recently, we reported that this enhancer is inhibited by serotonin type-1 (5-HT1) agonists, similar to currently used antimigraine drugs. We have now tested whether this repression involves a mitogen-activated protein (MAP) kinase pathway. We first demonstrate that the CGRP enhancer is strongly (10-fold) activated by a constitutively active MAP kinase kinase (MEK1), yielding reporter activities 100-fold above the enhancerless control. The involvement of a MAP kinase pathway was confirmed by down-regulation of reporter activity upon cotransfection of a dominant negative Ras. Activation of the enhancer by MEK1 was blocked in a dose-dependent manner by the 5-HT1 receptor agonist CGS 12066A (CGS). Since it is not known whether the CGRP enhancer factors are immediate targets of MAP kinases, we then used EIk-1- and c-Jun-dependent reporter genes that are directly activated by the ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinase) MAP kinases. CGS treatment repressed the activation of both of these reporters, suggesting that at least two MAP kinases are the immediate targets of CGS...Continue Reading

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Citations

Apr 25, 2006·The European Journal of Neuroscience·Jamie BellamyPaul L Durham
May 27, 2009·Molecular Neurobiology·Yong Chen, Claudia Sommer
Feb 26, 2005·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Patricia M Whitaker-Azmitia
Sep 10, 2009·Brain : a Journal of Neurology·Marie-Luise SixtMichael J M Fischer
Apr 3, 2001·The Journal of Biological Chemistry·J L Wood, A F Russo
Nov 10, 2001·Trends in Endocrinology and Metabolism : TEM·P R Albert, M Tiberi
Aug 23, 2002·Pharmacology & Therapeutics·Paul L Durham, Andrew F Russo

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