Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca2+ oscillations

Pecze, László; Blum, Walter; Henzi, Thomas; Schwaller, Beat

doi:10.1016/j.bbamcr.2016.09.013

Cited by 19 publications

(23 citation statements)

References 63 publications

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“…For instance, nanomolar CAPS concentrations suffice to evoke Ca 2+ responses in cell lines ectopically expressing TRPV1 [29,30], 0.5–1 μM CAPS is required to evoke Ca 2+ responses in TRPV1+ sensory neurons [31], but 10–50 μM CAPS are required to evoke Ca 2+ responses in cancer cells [13,32]; the latter endogenously expressing much lower levels of TRPV1 than TRPV1+ neurons [13]. Of note, CAPS exerts TRPV1-independent effects, however at concentrations above 250 μM [33].…”

Section: Introductionmentioning

confidence: 99%

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

et al. 2017

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There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 μM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 μM) either alone or together with CAPS (10 μM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 μM). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/ kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required.

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Section: Introductionmentioning

confidence: 99%

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

et al. 2017

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“…Intracellular Ca 2+ signaling, frequently in the form of Ca 2+ oscillations, activates specific enzymes and transcription factors in a cell, which are often involved in cell proliferation [76]. Ca 2+ signals are usually not restricted to individual cancer cells, but are propagated to neighboring cells in the form of intercellular Ca 2+ waves, usually Ca2+ trigger waves are observed [77]. Assuming that intra- and intercellular Ca 2+ signaling is the major way by which cells encode and transmit information, it is likely that during the passageway of a Ca 2+ wave, several Ca 2+ -dependent targets in affected cells would be activated and/or deactivated.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Gap Junctional Coupling on the Spatiotemporal Patterns of Ca2+ Signals and the Harmonization of Ca2+-Related Cellular Responses

et al. 2016

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Calcium ions (Ca2+) are important mediators of a great variety of cellular activities e.g. in response to an agonist activation of a receptor. The magnitude of a cellular response is often encoded by frequency modulation of Ca2+ oscillations and correlated with the stimulation intensity. The stimulation intensity highly depends on the sensitivity of a cell to a certain agonist. In some cases, it is essential that neighboring cells produce a similar and synchronized response to an agonist despite their different sensitivity. In order to decipher the presumed function of Ca2+ waves spreading among connecting cells, a mathematical model was developed. This model allows to numerically modifying the connectivity probability between neighboring cells, the permeability of gap junctions and the individual sensitivity of cells to an agonist. Here, we show numerically that strong gap junctional coupling between neighbors ensures an equilibrated response to agonist stimulation via formation of Ca2+ phase waves, i.e. a less sensitive neighbor will produce the same or similar Ca2+ signal as its highly sensitive neighbor. The most sensitive cells within an ensemble are the wave initiator cells. The Ca2+ wave in the cytoplasm is driven by a sensitization wave front in the endoplasmic reticulum. The wave velocity is proportional to the cellular sensitivity and to the strength of the coupling. The waves can form different patterns including circular rings and spirals. The observed pattern depends on the strength of noise, gap junctional permeability and the connectivity probability between neighboring cells. Our simulations reveal that one highly sensitive region gradually takes the lead within the entire noisy system by generating directed circular phase waves originating from this region.

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“…The activated inositol phospholipid pathway acts as an amplifier and frequency-based modulator on Ca 2+ signals produced by TRPV1. The frequency of the intracellular Ca 2+ oscillations are related to the strength of TRPV1 stimulation (Pecze et al, 2016a). Since exogenous TRPV1 ligands (CAP and RTX) have different pharmacological properties such as higher affinity and potency compared to endogenous agonists, they consequently induce an over-activity of the TRPV1 receptor.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons

2017

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“Molecular neurosurgery” is emerging as a new medical concept, and is the combination of two partners: (i) a molecular neurosurgery agent, and (ii) the cognate receptor whose activation results in the selective elimination of a specific subset of neurons in which this receptor is endogenously expressed. In general, a molecular surgery agent is a selective and potent ligand, and the target is a specific cell type whose elimination is desired through the molecular surgery procedure. These target cells have the highest innate sensitivity to the molecular surgery agent usually due to the highest receptor density being in their plasma membrane. The interaction between the ligand and its receptor evokes an overactivity of the receptor. If the receptor is a ligand-activated non-selective cation channel, the overactivity of receptor leads to excess Ca2+ and Na+ influx into the cell and finally cell death. One of the best known examples of such an interaction is the effect of ultrapotent vanilloids on TRPV1-expressing pain-sensing neurons. One intrathecal resiniferatoxin (RTX) dose allows for the receptor-mediated removal of TRPV1+ neurons from the peripheral nervous system. The TRPV1 receptor-mediated ion influx induces necrotic processes, but only in pain-sensing neurons, and usually within an hour. Besides that, target-specific apoptotic processes are also induced. Thus, as a nano-surgery scalpel, RTX removes the neurons responsible for generating pain and inflammation from the peripheral nervous system providing an option in clinical management for the treatment of morphine-insensitive pain conditions. In the future, the molecular surgery concept can also be exploited in cancer research for selectively targeting the specific tumor cell.

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Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca2+ oscillations

Cited by 19 publications

References 63 publications

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels

The Effect of Gap Junctional Coupling on the Spatiotemporal Patterns of Ca2+ Signals and the Harmonization of Ca2+-Related Cellular Responses

Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons

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