Pharmacological inhibition of TRPM8-induced gene transcription

Thiel, Gerald; Backes, Tobias M.; Welck, Jennifer; Steinhausen, Sebastian; Fischer, A.; Langfermann, Daniel S.; Ulrich, Myriam; Wissenbach, Ulrich; Rößler, Oliver G.

doi:10.1016/j.bcp.2019.113678

Cited by 13 publications

(13 citation statements)

References 49 publications

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“…In addition, at the immunohistochemical level, immunoreactivity for progesterone receptors was found to be widely distributed, including two synaptic layers (OPL and IPL) 23 . In previous studies, progesterone and pregnenolone were shown to act on TRP channels (TRPM1 42 , TRPM3 [43][44][45] , TRPC6 46 , and TRPM8 47 ), suggesting their stimulation of glutamatergic circuits via the activation of TRP family members. In the retina, TRPM3 is expressed in the inner retina (IPL and GCL) 48 and TRPM1 has been detected in the dendrites of rod bipolar cells 49 .…”

Section: Discussionmentioning

confidence: 91%

Effects of Gonadal Hormones On Glutamatergic Circuits in the Retina

Ohkuma

Maruyama

Ishii

et al. 2021

Preprint

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Gonadal hormones function as neurosteroids in the retina; however, their targets in the retina have not yet been identified. The present study examined the effects of gonadal hormones on glutamatergic circuits in the retina. Extracellular glutamate concentrations, which correspond to the amount of glutamate released, were monitored using an enzyme-linked fluorescent assay system. Progesterone and pregnenolone both increased extracellular glutamate concentrations at a physiological concentration in pregnancy, whereas estrogen and testosterone did not. Synaptic level observations using a patch clamp technique revealed that progesterone increased the activity of glutamatergic synapses. We also investigated whether high concentrations of gonadal hormones induced changes in the retina during pregnancy. The present results indicate that progesterone activates glutamatergic circuits as a neurosteroid when its concentration is elevated in pregnancy.

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Section: Discussionmentioning

confidence: 91%

Effects of Gonadal Hormones On Glutamatergic Circuits in the Retina

Ohkuma

Maruyama

Ishii

et al. 2021

Preprint

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“…ERK1/2 is activated by a rise in intracellular Ca 2+ [3][4][5][6][7][8][9][10][11], most likely involving the protein kinases PKC and Raf. The key role of ERK1/2 as a cytoplasmic signal transducer connecting a rise in cytoplasmic Ca 2+ and the activation of gene transcription has been confirmed by pharmacological or genetic inhibition of the ERK1/2 signaling cascade [10,[12][13][14][15], or overexpression experiments involving MAP kinase phosphatase-1 and DA-Raf-1 [8,9,16,17], a splice form of A-Raf that functions as a dominant negative inhibitor of Raf. The MAP kinases c-Jun N-terminal protein kinase (JNK) and p38 have also been identified as signal transducers [10,18,19].…”

Section: Signal Transducers Required For Ca 2+ -Induced Signaling From the Plasma Membrane To The Nucleusmentioning

confidence: 96%

Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

Thiel

Schmidt

Rößler

2021

Cells

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Ca2+ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca2+ concentration upon stimulation. The elevated Ca2+ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca2+ at different locations in the cell. Ca2+ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca2+ ions. A major function of the rise in intracellular Ca2+ is the change of the genetic expression pattern of the cell via the activation of Ca2+-responsive transcription factors. It has been proposed that Ca2+-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca2+. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca2+ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca2+ induces an intracellular signaling cascade, involving the activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca2+/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca2+ concentration in the cytoplasm and the nucleus, the role of Ca2+ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca2+ signaling and gene expression.

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“…2 identified as an intracellular signal transducter [13]. In addition, calmodulin, calcineurin, and phospholipase C (PLC) β have been identified as important molecules that enable signal transduction from the plasma membran to the nucleus after TRPM8 channel stimulation [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have shown that stimulation of TRPM8 channels activates the transcription factor AP-1 [13,24]. AP-1 is composed of two basic region leucine zipper (bZIP) transcription factors of the Jun, Fos and ATF families of transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Signal Transduction of Transient Receptor Potential TRPM8 Channels: Role of PIP5K, Gq-Proteins, and c-Jun

Thiel,

Rössler

2024

Preprint

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Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and “cooling agents” such as menthol and icilin, which induce a cold sensation. Stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigated the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that inhibition of phosphatidylinositol 4-phosphate 5 kinase alpha (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuated TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that pharmacological inhibition of the beta gamma subunits impairs TRPM8 signaling. In addition, genetic studies showed that TRPM8 requires an activated Galpha subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers an activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identified the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signling cscade. In summary, with PIP5K, Gq subunits and c-Jun we have identified key molecules in the TRPM8-induced signaling from the plasma membrane to the nucleus.

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Pharmacological inhibition of TRPM8-induced gene transcription

Cited by 13 publications

References 49 publications

Effects of Gonadal Hormones On Glutamatergic Circuits in the Retina

Effects of Gonadal Hormones On Glutamatergic Circuits in the Retina

Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

Signal Transduction of Transient Receptor Potential TRPM8 Channels: Role of PIP5K, Gq-Proteins, and c-Jun

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