TRP channels: novel gating properties and physiological functions

Nilius, Bernd; Sage, Stewart O.

doi:10.1113/jphysiol.2005.093245

Cited by 20 publications

(5 citation statements)

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“…Quite in contrast, the HICC in the human cervix carcinoma cell line HeLa is clearly insensitive to amiloride (in concentrations up to 100 μ m ) and the only lead with regard to its molecular identity obtained so far is a partial inhibition by (100 μ m ) SKF‐96365 (Wehner et al 2003 b ), a largely unspecific blocker of TRP (‘transient‐receptor potential’) channels (Pena & Ordaz, 2008). Nevertheless, TRP channels are found in numerous tissues and they are known to be specialized in various forms of sensorial perception rendering them potential candidates for (direct or indirect) volume detectors and/or effectors (Nilius & Sage, 2005; Owsianik et al 2006 b ; Pedersen & Nilius, 2007). Of considerable interest, in this respect, is the identification of TRPM7 as the stretch‐ and swelling‐activated channel (SACC) in HeLa cells mediating the Ca 2+ signal in the ‘regulatory volume decrease’ (RVD) response to osmotically induced swelling (Numata et al 2007 a ).…”

Section: Introductionmentioning

confidence: 99%

The ΔC splice‐variant of TRPM2 is the hypertonicity‐induced cation channel in HeLa cells, and the ecto‐enzyme CD38 mediates its activation

Numata

Sato

Christmann

et al. 2012

The Journal of Physiology

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Key points• Hypertonicity-induced cation channels (HICCs) are key players in proliferation and apoptosis but their molecular identity has remained elusive.• We report that in HeLa cells, intracellular adenosine diphosphate ribose (ADPr) and cyclic ADPr (cADPr), as activators of TRPM2 cation channels, elicited currents that are identical to the osmotic activation of HICCs.• siRNA-mediated silencing of the expression of TRPM2 and CD38 (as the supposed source of ADPr and cADPr) inhibited HICC and nucleotide-induced currents and the osmotic volume response of cells.• Quantification of intracellular cADPr and extracellular application of nucleotides revealed that the outwardly directed gradient rather than the intracellular activity of ADPr and cADPr is the triggering factor for TRPM2.• Cloning of TRPM2 identified the C-splice variant as the molecular correlate of the HICC, which was supported by quantification of Ca 2+ selectivity.• Immunoprecipation and FRET/FLIM assays revealed the interaction of TRPM2 and CD38 and we propose a transport-related nucleotide export via CD38 as a novel mechanism of TRPM2 activation.Abstract Hypertonicity-induced cation channels (HICCs) are key-players in proliferation and apoptosis but their molecular correlate remains obscure. Furthermore, the activation profile of HICCs is not well defined yet. We report here that, in HeLa cells, intracellular adenosine diphosphate ribose (ADPr) and cyclic ADPr (cADPr), as supposed activators of TRPM2, elicited cation currents that were virtually identical to the osmotic activation of HICCs. Silencing of the expression of TRPM2 and of the ecto-enzyme CD38 (as a likely source of ADPr and cADPr) inhibited HICC as well as nucleotide-induced currents and, in parallel, the hypertonic volume response of cells (the regulatory volume increase, RVI) was attenuated. Quantification of intracellular cADPr levels and the systematic application of extra-vs. intracellular nucleotides indicate that the outwardly directed gradient rather than the cellular activity of ADPr and cADPr triggers TRPM2 activation, probably along with a simultaneous biotransformation of nucleotides. Cloning of TRPM2 identified the C-splice variant as the molecular correlate of the HICC, which could be strongly supported by a direct comparison of the respective Ca 2+ selectivity. Finally, immunoprecipitation and high-resolution FRET/FLIM imaging revealed the interaction of TRPM2 and K. Sato and J. Christmann contributed equally to this work. CD38 in the native as well as in a heterologous (HEK293T) expression system. We propose transport-related nucleotide export via CD38 as a novel mechanism of TRPM2/HICC activation. With the biotransformation of nucleotides running in parallel, continuous zero trans-conditions are achieved which will render the system infinitely sensitive. (

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Section: Introductionmentioning

confidence: 99%

The ΔC splice‐variant of TRPM2 is the hypertonicity‐induced cation channel in HeLa cells, and the ecto‐enzyme CD38 mediates its activation

Numata

Sato

Christmann

et al. 2012

The Journal of Physiology

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“…Overall, our computational modelling data are in agreement with our in vivo results. In similar manner, several groups have generated homology models for the pore-forming region of TRPV1, TRPV3, TRPV6, TRPC3, TRPA1, TRPM4, Drosophila TRP and yeast TRPY1 (refs 1 , 43 , 53 , 54 , 55 ). These structural models have served as illustrations of the respective channels’ biophysics.…”

Section: Resultsmentioning

confidence: 99%

“…Since their discovery in fly phototransduction, transient receptor potential (TRP) ion channels have been found to critically function in neurosensory transduction across phyla except in plants and bacteria 1 2 . They have a role in several sensory submodalities, including osmotic, thermal, mechanical, photo (including ultraviolet radiation) and acid sensing 3 4 5 6 7 8 9 10 11 12 .…”

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confidence: 99%

“…Of note, both subfamilies have been linked to pain signalling and are known to conduct Ca 2+ (refs 5 , 15 , 24 , 25 ). Most of these channels show an increased selectivity for Ca 2+ over Na + (refs 1 , 16 , 26 , 27 , 28 ), presumably as a function of the selectivity filter. In sharp contrast to the pivotal relevance of the selectivity filter for the biophysical function of the channel, as established by cellular studies, investigations of the presumed selectivity filter region in live animals are largely missing.…”

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confidence: 99%

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TRPV channel-mediated calcium transients in nociceptor neurons are dispensable for avoidance behaviour

et al. 2014

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Animals need to sense and react to potentially dangerous environments. TRP ion channels participate in nociception, presumably via Ca2+ influx, in most animal species. However, the relationship between ion permeation and animals’ nocifensive behaviour is unknown. Here we use an invertebrate animal model with relevance for mammalian pain. We analyse the putative selectivity filter of OSM-9, a TRPV channel, in osmotic avoidance behaviour of Caenorhabditis elegans. Using mutagenized OSM-9 expressed in the head nociceptor neuron, ASH, we study nocifensive behaviour and Ca2+ influx. Within the selectivity filter, M601-F609, Y604G strongly reduces avoidance behaviour and eliminates Ca2+ transients. Y604F also abolishes Ca2+ transients in ASH, while sustaining avoidance behaviour, yet it disrupts behavioral plasticity. Homology modelling of the OSM-9 pore suggests that Y604 may assume a scaffolding role. Thus, aromatic residues in the OSM-9 selectivity filter are critical for pain behaviour and ion permeation. These findings have relevance for understanding evolutionary roots of mammalian nociception.

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“…Downregulation of Grin1 and Gria 2 might decrease calcium concentration after a longer time, influencing neuronal survival (Guo and Ma, 2021 ). Several TRP channels are involved in sensory functions (Nilius et al, 2003 ; Voets et al, 2004 , 2005 ; Nilius and Sage, 2005 ), and their expression or functional changes alter neuronal responsiveness (Nilius and Owsianik, 2011 ). TRPM 3,7,8 were downregulated 24 h after 500 nM HK-1, which is the opposite of what we earlier found in response to another sensory neuropeptide, PACAP (Takács-Lovász et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Hemokinin-1 induces transcriptomic alterations in pain-related signaling processes in rat primary sensory neurons independent of NK1 tachykinin receptor activation

Takács-Lovász,

Aczél,

Borbély

et al. 2023

Front. Mol. Neurosci.

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The tachykinin hemokinin-1 (HK-1) is involved in immunological processes, inflammation, and pain. Although the neurokinin 1 receptor (NK1R) is described as its main target, several effects are mediated by currently unidentified receptor(s). The role of HK-1 in pain is controversial, depending on the involvement of peripheral and central sensitization mechanisms in different models. We earlier showed the ability of HK-1 to activate the trigeminovascular system, but the mechanisms need to be clarified. Therefore, in this study, we investigated HK-1-induced transcriptomic alterations in cultured rat trigeminal ganglion (TRG) primary sensory neurons. HK-1 was applied for 6 or 24 h in 1 μM causing calcium-influx in these neurons, 500 nM not inducing calcium-entry was used for comparison. Next-generation sequencing was performed on the isolated RNA, and transcriptomic changes were analyzed to identify differentially expressed (DE) genes. Functional analysis was performed for gene annotation using the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. NK1R and Neurokinin receptor 2 (NK2R) were not detected. Neurokinin receptor 3 (NK3R) was around the detection limit, which suggests the involvement of other NKR isoforms or other receptors in HK-1-induced sensory neuronal activation. We found protease-activated receptor 1 (PAR1) and epidermal growth factor receptor (EGFR) as DE genes in calcium signaling. The transmembrane protein anthrax toxin receptor 2 (ANTXR2), a potential novel pain-related target, was upregulated. Acid-sensing ion channel 1; 3 (Asic1,3), N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors decreased, myelin production and maintenance related genes (Mbp, Pmp2, Myef2, Mpz) and GNDF changed by HK-1 treatment. Our data showed time and dose-dependent effects of HK-1 in TRG cell culture. Result showed calcium signaling as altered event, however, we did not detect any of NK receptors. Presumably, the activation of TRG neurons is independent of NK receptors. ANTXR2 is a potential new target, PAR-1 has also important role in pain, however their connection to HK-1 is unknown. These findings might highlight new targets or key mediators to solve how HK-1 acts on TRG.

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TRP channels: novel gating properties and physiological functions

Cited by 20 publications

References 4 publications

The ΔC splice‐variant of TRPM2 is the hypertonicity‐induced cation channel in HeLa cells, and the ecto‐enzyme CD38 mediates its activation

The ΔC splice‐variant of TRPM2 is the hypertonicity‐induced cation channel in HeLa cells, and the ecto‐enzyme CD38 mediates its activation

TRPV channel-mediated calcium transients in nociceptor neurons are dispensable for avoidance behaviour

Hemokinin-1 induces transcriptomic alterations in pain-related signaling processes in rat primary sensory neurons independent of NK1 tachykinin receptor activation

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