PT  - JOURNAL ARTICLE
AU  - Andrea Lesch
AU  - Xin Hui
AU  - Peter Lipp
AU  - Gerald Thiel
TI  - Transient Receptor Potential Melastatin-3 (TRPM3)-Induced Activation of AP-1 Requires Ca2+ ions and the Transcription Factors c-Jun, ATF2, and TCF
AID  - 10.1124/mol.114.095695
DP  - 2015 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.095695
4099  - http://molpharm.aspetjournals.org/content/early/2015/01/09/mol.114.095695.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/01/09/mol.114.095695.full
AB  - The steroid pregnenolone sulfate activates the transcription factor activator protein-1 (AP-1) via stimulation of transient receptor potential melastatin-3 (TRPM3) channels. Here, we show that the signaling pathway requires an influx of Ca2+ ions into the cells and a rise in the intracellular Ca2+ levels. The upregulation of AP-1 was attenuated in cells that overexpressed MAP kinase phosphatase (MKP)-1, indicating that Ca2+ ions prolong the signaling cascade via activation of MAP kinases. On the transcriptional level, expression of a dominant-negative mutant of the basic region leucine zipper (bZIP) protein c-Jun, a major constituent of the AP-1 transcription factor complex, or expression of a c-Jun-specific small-hairpin (sh) RNA attenuated pregnenolone sulfate-induced AP-1 activation. In addition, stimulation of TRPM3 channels increased the transcriptional activation potential of the bZIP protein ATF2. Inhibition of ATF2 target gene expression via expression of a dominant-negative mutant of ATF2 or expression of an ATF2-specific shRNA interfered with TRPM3-mediated stimulation of AP-1. Moreover, we show that a dominant-negative mutant of the ternary complex factor (TCF) Elk-1 attenuated the upregulation of AP-1 following stimulation of TRPM3 channels. Thus, c-Jun, ATF2 and TCFs are required to connect the intracellular signaling cascade elicited by activation of TRPM3 channels with enhanced transcription of AP-1 regulated genes. We conclude that pregnenolone sulfate-induced TRPM3 channel activation changes the gene expression pattern of the cells by activating transcription of c-Jun, ATF2 and TCF controlled genes.