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  • br Conclusion We present here the first comprehensive

    2023-01-30


    Conclusion We present here the first comprehensive analysis of B-Raf-induced transcriptional activation in insulinoma cells. The B-Raf-induced signaling cascade targets the c-Fos and the c-Jun genes. Both gene products are constituents of the AP-1 transcription factor. The phosphatases MKP-1 and calcineurin are part of a negative feedback loop that attenuates AP-1 activation following B-Raf stimulation. The signaling pathway connecting B-Raf with AP-1 and an AP-1-regulated delayed response gene is depicted in Fig. 9. An important aim of future research will be the identification of further AP-1-regulated genes in insulinoma cetyltrimethylammonium bromide and pancreatic β-cells.
    Conflict of interest
    Acknowledgements We thank Hindrik Mulder, Lund University, Sweden, for INS-1 832/13 cells. We thank Libby Guethlein for critical reading of the manuscript. This study was supported by the Saarland University, Germany (LOM-T201000492).
    Introduction Transient receptor potential vanilloid 1 (TRPV1) channels belong to the familiy of TRP non-selective cation channels. TRPV1 has the typical TRP modular structure with six transmembrane domains. The central ion channel is formed by the transmembrane regions 5 and 6. Both N- and C-termini are located in the cytosol [1]. Numerous ligands have been identified that activate TRPV1 channels [1], [2]. Most prominent, TRPV1 is activated by capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a vanilloid derived from hot chilli pepper (Capsicum annuum). In fact, TRPV1 was initially identified by expression cloning as a capsaicin receptor [3]. The vanilloid resiniferatoxin from Euphorbia resinifera is also highly active in stimulation of TRPV1 channels. Various lipids function as endogenous ligands for TRPV1, including N-arachidonylethanolamine (anandamide), N-arachidonoyldopamine (NADA), Noleoyldopamine, and leukotriene B4 [4]. TRPV1 is prominently expressed in trigeminal and dorsal root sensory ganglia, particular in peptidergic somatosensory neurons. TRPV1 is also expressed outside the nervous system, e. g. in the kidney and in the gastrointestinal tract. TRPV1 belongs to the thermoTRPs that sense thermal changes of the environment resulting in sensory nerve impulses. Gene targeting experiments revealed that TRPV1 channels are required for pain sensation and for tissue injury-induced inflammatory thermal hyperalgesia. Thus, TRPV1 plays an essential role in pain hypersensitivity which is associated with chronic pain conditions [5], [6]. Activation of TRPV1 channels triggers the secretion of the pro-inflammatory neuropeptides substance P and calcitonin gene-related peptide from peripheral neuronal termini, thus initiating neurogenic inflammation [7]. TRPV1 is also involved in pain conditions associated with inflammation in the gastrointestinal tract [8]. According to its prominent role in pain sensation, TRPV1 is a well studied drug target and TRPV1 antagonists have been suggested for use in the treatment of migraine, chronic intractable pain secondary to cancer, AIDS, diabetes, urinary urge incontinence, chronic cough and irritable bowel syndrome [9]. We previously showed that stimulation of TRPM3 and TRPC6 channels activated stimulus-responsive transcription factors [10], [11], [12], [13], [14], [15]. Therefore, we asked whether stimulation of TRPV1 channels leads to a change in gene transcription as well. Here, we show that stimulation of human TRPV1 channels with the plant-derived compounds capsaicin and resiniferatoxin, or the natural TRPV1 ligand NADA increased the biosynthesis of the basic region-leucine zipper (bZIP) transcription factors c-Fos and c-Jun and activated the AP-1 transcription factor. AP-1 (activator protein-1) is a dimer of proteins from the Fos, Jun and ATF transcription factor families. The results of this study show that the TRPV1 ligands capsaicin and resiniferatoxin induced an influx of Ca2+ into the cells and this rise in intracellular Ca2+ was essential to couple TRPV1 stimulation with the AP-1 transcription factor. The TRPV1 ligand NADA increased the intracellular Ca2+ concentration in a TRPV1-dependent and TRPV1-independent manner. Accordingly, stimulation of the cells with NADA activated AP-1 in a TRPV1-dependent and TRPV1-independent manner. We identified extracellular signal-regulated protein kinase as signal transducer and showed that AP-1 activation required the transcription factors c-Jun and TCF following stimulation of TRPV1 channels. Together, our data show that stimulation of TRPV1 channels leads to alternations in the gene expression pattern. In particular, as AP-1 is involved in the regulation of proliferation, transformation, differentiation, and programmed cell death in a tissue-specific manner [16], our data link TRPV1 stimulation to the biological functions of AP-1.