Stimulation of TRPV1 channels activates the AP-1 transcription factor

Backes, Tobias M.; Rößler, Oliver G.; Hui, Xin; Grötzinger, Carsten; Lipp, Peter; Thiel, Gerald

doi:10.1016/j.bcp.2018.02.008

Cited by 23 publications

(9 citation statements)

References 44 publications

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“…The authors stated that regulation of gene transcription is an integral part of calcium-sensing receptor induced signaling. Comparable results were reported by Backes et al (2018), who found that stimulation of TRPV1 channels (which play a role in pain sensation and inflammatory thermal hyperalgesia) by capsicain or resiniferatoxin induced an influx of Ca 2+ into the cells, and that this rise in [Ca 2+ ]i is essential for activating transcription factor AP-1.…”

Section: Nuclear Receptors For Farnesol Its Esters (= Jhs) and Metabsupporting

confidence: 53%

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

Loof

Schoofs

2019

Front. Neurosci.

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Farnesol, the sesquiterpenoid precursor of insect juvenile hormones (JH) that itself has JH activity, existed already long before animals and their hormones came into being. Although it is omnipresent in all eukaryotes, this molecule remains a “noble unknown” in cell physiology. It is neither documented as a hormone nor as another type of signaling molecule. To date, its function as an intermediate in the synthesis of squalene-cholesterol-steroids in chordates/vertebrates, and of the insect/arthropod JHs, esters of farnesol, in the mevalonate biosynthetic pathway is assumed to be the only one. This assumption neglects that already two decades ago, farnesol has been shown to be a potent endogenous inhibitor of N-type voltage-gated Ca 2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca 2+ channels originated early in eukaryotic evolution, and has since been well conserved, “promoting” it as a ubiquitous player in Ca 2+ homeostasis in all eukaryotes. This paper accentuates how this drastic change in thinking gained momentum after the discovery by Paroulek and Sláma that the huge amounts of JH I in male accessory glands of the Cecropia moth, are actually synthesized in these glands themselves and not in the corpora allata, the hitherto assumed unique synthesis site of such compounds. In addition, MAG-JHs have no hormonal- but an exocrine function. Here we hypothesize that MAG-JHs may function in protecting the spermatozoa against toxic Ca 2+ concentrations, and in enabling their flagellum to undulate. They may do so by acting through membrane receptors. Our novel paradigm assigns to farnesol/JHs a function of flexible hydrophobic molecular valves for restricting untimely Ca 2+ -passage through some types of canonical Ca 2+ channels, using covalently bound farnesyl- or geranyl-geranyl group attachment as well as GPCRs-G proteins all containing a prenyl group. The high rotatable bond count, and their horseshoe-shape are instrumental to their valve function. In our paradigm, Met/Tai and Gce, to date generally thought to be the (only) functional (nuclear) receptors for JHs, are classified as probable Ca 2+ -sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed.

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Section: Nuclear Receptors For Farnesol Its Esters (= Jhs) and Metabsupporting

confidence: 53%

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

Loof

Schoofs

2019

Front. Neurosci.

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“…It has been found that the activation of MAPK may participate in generating pain hypersensitivity and that MEK inhibitors known to suppress phosphorylation of ERK can effectively alleviate pain at various time points in several animal models of neuropathic pain [ 26 , 27 ]. It has been reported that stimulation of TRPV1 with capsaicin leads to a rapid phosphorylation and activation of ERK1/2 [ 28 ]. Morphine was found to induce ERK activation in CHO cells stably transfected with MOR [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

β-Arrestin 2 and ERK1/2 Are Important Mediators Engaged in Close Cooperation between TRPV1 and µ-Opioid Receptors in the Plasma Membrane

Melkes

Marková

Hejnova

et al. 2020

IJMS

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The interactions between TRPV1 and µ-opioid receptors (MOR) have recently attracted much attention because these two receptors play important roles in pain pathways and can apparently modulate each other’s functioning. However, the knowledge about signaling interactions and crosstalk between these two receptors is still limited. In this study, we investigated the mutual interactions between MOR and TRPV1 shortly after their activation in HEK293 cells expressing these two receptors. After activation of one receptor we observed significant changes in the other receptor’s lateral mobility and vice versa. However, the changes in receptor movement within the plasma membrane were not connected with activation of the other receptor. We also observed that plasma membrane β-arrestin 2 levels were altered after treatment with agonists of both these receptors. Knockdown of β-arrestin 2 blocked all changes in the lateral mobility of both receptors. Furthermore, we found that β-arrestin 2 can play an important role in modulating the effectiveness of ERK1/2 phosphorylation after activation of MOR in the presence of TRPV1. These data suggest that β-arrestin 2 and ERK1/2 are important mediators between these two receptors and their signaling pathways. Collectively, MOR and TRPV1 can mutually affect each other’s behavior and β-arrestin 2 apparently plays a key role in the bidirectional crosstalk between these two receptors in the plasma membrane.

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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

Self Cite

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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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Stimulation of TRPV1 channels activates the AP-1 transcription factor

Cited by 23 publications

References 44 publications

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

β-Arrestin 2 and ERK1/2 Are Important Mediators Engaged in Close Cooperation between TRPV1 and µ-Opioid Receptors in the Plasma Membrane

Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

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