title: Extracellular Signal-Regulated Protein Kinase, c-Jun N-Terminal Protein Kinase, and Calcineurin Regulate Transient Receptor Potential M3 (TRPM3) Induced Activation of AP-1.
abstract: Stimulation of transient receptor potential M3 (TRPM3) cation channels with pregnenolone sulfate induces an influx of Ca2+ions into the cells and a rise in the intracellular Ca2+concentration, leading to the activation of the activator protein-1 (AP-1) transcription factor. Here, we show that expression of a constitutively active mutant of the Ca2+/calmodulin-dependent protein phosphatase calcineurin attenuated pregnenolone sulfate-induced AP-1 activation in TRPM3-expressing cells. Likewise, expression of the regulatory B subunit of calcineurin reduced AP-1 activity in the cells following stimulation of TRPM3 channels. MAP kinase phosphatase-1 has been shown to attenuate TRPM3-mediated AP-1 activation. Here, we show that pregnenolone sulfate-induced stimulation of TRPM3 triggers the phosphorylation and activation of the MAP kinase extracellular signal-regulated protein kinase (ERK1/2). Pharmacological and genetic experiments revealed that stimulation of ERK1/2 is essential for the activation of AP-1 in cells expressing stimulated TRPM3 channels. ERK1/2 is required for the activation of the transcription factor c-Jun, a key component of the AP-1 transcription factor, and regulates c-Fos promoter activity. In addition, we identified c-Jun N-terminal protein kinase (JNK1/2) as a second signal transducer of activated TRPM3 channels. Together, the data show that calcineurin and the protein kinases ERK1/2 and JNK1/2 are important regulators within the signaling cascade connecting TRPM3 channel stimulation with increased AP-1-regulated transcription. J. Cell. Biochem. 118: 2409-2419, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Saarland University, Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lesch
authors.affiliation: Saarland University, Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany.
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Rössler
authors.affiliation: Saarland University, Medical Faculty, Department of Medical Biochemistry and Molecular Biology, D-66421 Homburg, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
mesh_terms: D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011284:Pregnenolone / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C475667:TRPM3 protein, human; D018808:Transcription Factor AP-1; C018370:pregnenolone sulfate; D011284:Pregnenolone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019703:Calcineurin
keywords: CALCINEURIN; ERK; JNK; PREGNENOLONE SULFATE; TRPM3; c-JUN