Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5-HT2A receptors
✍ Scribed by Margarete Goppelt-Struebe; Martin Stroebel
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 202 KB
- Volume
- 175
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Signaling pathways responsible for serotonin (5-HT)-mediated induction of early response genes prostaglandin G/H synthase-2 (PGHS-2, cyclooxygenase-2) and egr-1 were investigated in rat mesangial cells. Gene induction by 5-HT was dependent on 5-HT 2A receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the G q family. Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C (PLC) and release of Ca 2/ from internal stores, but this activation was not related to PGHS-2 mRNA expression. Similarly, PI-3 kinase was not involved in 5-HT signaling. Instead, inhibition of phosphatidylcholine-specific PLC interfered with PGHS-2 and egr-1 mRNA induction, suggesting this enzyme as a link between 5-HT 2A receptors and protein kinase C, an essential part of 5-HT-mediated signaling. The MAP kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression. Increase of intracellular cAMP by forskolin or dibutyryl cAMP did not induce PGHS-2 or egr-1 mRNA expression by itself, but strongly inhibited 5-HT-mediated mRNA induction. PGHS-2 mRNA and protein induction by 5-HT was also abolished by chelation of Ca 2/ ions by EGTA, suggesting involvement of Ca 2/ -dependent enzymes. In contrast, egr-1 mRNA expression was superinduced in the presence of EGTA. Induction of Egr-1 protein was not changed by EGTA hinting to Ca 2/ -sensitive posttransscriptional steps. Activation of the G qcoupled 5-HT 2A receptor thus leads to the expression of the early response genes PGHS-2 and egr-1, using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells, respectively.