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Repression of the Calcitonin Gene-Related Peptide Promoter by 5-HT1 Receptor Activation
Journal article   Open access   Peer reviewed

Repression of the Calcitonin Gene-Related Peptide Promoter by 5-HT1 Receptor Activation

Paul L Durham, Ram V Sharma and Andrew F Russo
The Journal of neuroscience, Vol.17(24), pp.9545-9553
12/15/1997
DOI: 10.1523/JNEUROSCI.17-24-09545.1997
PMID: 9391009
url
https://doi.org/10.1523/JNEUROSCI.17-24-09545.1997View
Published (Version of record) Open Access

Abstract

We have investigated the control of calcitonin gene-related peptide (CGRP) expression by a serotonergic agonist that is related pharmacologically to currently used antimigraine drugs. During migraines, CGRP levels are elevated but then returned to normal by a 5-HT 1 receptor agonist, sumatriptan. However, neither the molecular nor cellular targets of this drug are known. Trigeminal neurons are the major source of cerebrovascular CGRP, and thus we have used trigeminal primary cultures and the neuronal-like CA77 thyroid C-cell line as a model. We first demonstrate that sumatriptan and another 5-HT 1 agonist, CGS 12066A (CGS), cause a robust and prolonged increase with oscillations in intracellular calcium in CA77 cells. CGS caused a similar increase in trigeminal cultures. We then show that CGS treatment leads to a decrease in CGRP mRNA levels in the CA77 cells. This decrease is attributable to the repression of promoter activity through two discrete elements: (1) the cAMP-responsive region, via a cAMP-independent mechanism; and (2) the cell-specific enhancer, which binds the upstream stimulatory factor helix–loop–helix protein and a cell-specific activator. These results demonstrate that activation of the endogenous 5-HT 1 receptor is coupled to calcium signaling pathways and leads to inhibition of CGRP gene transcription.
 5-HT1 receptor serotonin thyroid C-cells calcium transcription trigeminal CGRP sumatriptan

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