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Volume 17, Number 24, Issue of December 15, 1997 pp. 9545-9553

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

Received June 10, 1997; revised Sept. 15, 1997; accepted Sept. 25, 1997.

Paul L. Durham¹, Ram V. Sharma², and Andrew F. Russo¹

Departments of ¹ Physiology and Biophysics and ² Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242

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-HT₁ 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-HT₁ 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-HT₁ receptor is coupled to calcium signaling pathways and leads to inhibition of CGRP gene transcription.

Key words: CGRP; transcription; trigeminal; thyroid C-cells; serotonin; 5-HT₁ receptor; sumatriptan; calcium

This article has been cited by other articles:

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				P. L. Durham and A. F. Russo Stimulation of the Calcitonin Gene-Related Peptide Enhancer by Mitogen-Activated Protein Kinases and Repression by an Antimigraine Drug in Trigeminal Ganglia Neurons J. Neurosci., February 1, 2003; 23(3): 807 - 815. [Abstract] [Full Text] [PDF]

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				P. L. Durham and A. F. Russo Regulation of Calcitonin Gene-Related Peptide Secretion by a Serotonergic Antimigraine Drug J. Neurosci., May 1, 1999; 19(9): 3423 - 3429. [Abstract] [Full Text] [PDF]

				K. Suzuki, S. Lavaroni, A. Mori, F. Okajima, S. Kimura, R. Katoh, A. Kawaoi, and L. D. Kohn Thyroid Transcription Factor 1 Is Calcium Modulated and Coordinately Regulates Genes Involved in Calcium Homeostasis in C Cells Mol. Cell. Biol., December 1, 1998; 18(12): 7410 - 7422. [Abstract] [Full Text]

				P. L. Durham and A. F. Russo Serotonergic Repression of Mitogen-Activated Protein Kinase Control of the Calcitonin Gene-Related Peptide Enhancer Mol. Endocrinol., July 1, 1998; 12(7): 1002 - 1009. [Abstract] [Full Text]

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