Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells

Nilius, Bernd; Prenen, Jean; Wissenbach, Ulrich; Bödding, Matthias; Droogmans, Guy

doi:10.1007/s004240100676

Cited by 127 publications

(85 citation statements)

References 26 publications

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“…1 A and 7A). This higher basal [Ca 2ϩ ] i can be attributed to the basal TRPV4 channel activity in the absence of stimuli (11,12,33). The finding that [Ca 2ϩ ] i in nonstimulated cells is not significantly affected by preincubation with the various PLA 2 blockers (Fig.…”

Section: Hypotonicity-induced Activation Of Trpv4 Is Not Mediated By mentioning

confidence: 80%

“…They are distributed widely in mammalian tissues, but their specific physiological functions and activation mechanisms are often unclear. TRPV4, a member of the TRPV subfamily, was originally considered as a Ca 2ϩ -permeable sensor of cell volume (11)(12)(13)19), but later reports demonstrated that it can also be activated by phorbol esters (5), moderate heat (6,20), and AA metabolites (22). It is presently unknown how these completely different stimuli converge on a single molecular event: the opening of the TRPV4 conduction pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The TRPV subfamily can be subdivided into two groups. One group is formed by TRPV1-TRPV4, which display a moderate Ca 2ϩ selectivity (P Ca ͞P Na Ͻ 10, in which P is permeability), a weak field-strength monovalent cation permeability sequence, and steep temperature dependence (5,6,(11)(12)(13)(14)(15)(16). The second group is formed by TRPV5 and TRPV6, which are highly Ca 2ϩ selective (P Ca ͞P Na Ͼ 100) and display a permeability sequence for monovalent cations consistent with a strong field-strength binding site but show little temperature dependence (10,17,18).…”

mentioning

confidence: 99%

“…Studies addressing the gating mechanism of TRPV4 by cell swelling exclude potential pathways such as membrane stretch (11), intracellular ionic strength, and G proteins (12). In a recent study, evidence was presented that activation of TRPV4 by hypotonicity involves its phosphorylation by Lyn, a member of the Src family of tyrosine kinases (25).…”

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confidence: 99%

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Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4

Vriens

Watanabe

Janssens

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

571

532

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TRPV4 is a Ca 2؉ -and Mg 2؉ -permeable cation channel within the vanilloid receptor subgroup of the transient receptor potential (TRP) family, and it has been implicated in Ca 2؉ -dependent signal transduction in several tissues, including brain and vascular endothelium. TRPV4-activating stimuli include osmotic cell swelling, heat, phorbol ester compounds, and 5 ,6 -epoxyeicosatrienoic acid, a cytochrome P450 epoxygenase metabolite of arachidonic acid (AA). It is presently unknown how these distinct activators converge on opening of the channel. Here, we demonstrate that blockers of phospholipase A 2 (PLA2) and cytochrome P450 epoxygenase inhibit activation of TRPV4 by osmotic cell swelling but not by heat and 4␣-phorbol 12,13-didecanoate. Mutating a tyrosine residue (Tyr-555) in the N-terminal part of the third transmembrane domain to an alanine strongly impairs activation of TRPV4 by 4␣-phorbol 12,13-didecanoate and heat but has no effect on activation by cell swelling or AA. We conclude that TRPV4-activating stimuli promote channel opening by means of distinct pathways. Cell swelling activates TRPV4 by means of the PLA 2-dependent formation of AA, and its subsequent metabolization to 5 ,6 -epoxyeicosatrienoic acid by means of a cytochrome P450 epoxygenase-dependent pathway. Phorbol esters and heat operate by means of a distinct, PLA 2-and cytochrome P450 epoxygenase-independent pathway, which critically depends on an aromatic residue at the N terminus of the third transmembrane domain.T he TRPV subfamily of the transient receptor potential (TRP) family of cation channels consists of at least six mammalian channels homologous to the vanilloid receptor (for a unifying nomenclature, see ref. 1). The TRPV channels are activated by a variety of signals, including chemical and thermal stimuli, cell swelling, low intracellular Ca 2ϩ , and endogenous or synthetic ligands (2-10). Members of this subfamily contain a hydrophobic core region comprising six putative transmembrane segments (TM1-TM6), a pore-loop region between TM5 and TM6, a cytoplasmic N terminus with three to six ankyrin repeats, and a cytoplasmic C terminus (1, 3). The TRPV subfamily can be subdivided into two groups. One group is formed by TRPV1-TRPV4, which display a moderate Ca 2ϩ selectivity (P Ca ͞P Na Ͻ 10, in which P is permeability), a weak field-strength monovalent cation permeability sequence, and steep temperature dependence (5,6,(11)(12)(13)(14)(15)(16). The second group is formed by TRPV5 and TRPV6, which are highly Ca 2ϩ selective (P Ca ͞P Na Ͼ 100) and display a permeability sequence for monovalent cations consistent with a strong field-strength binding site but show little temperature dependence (10,17,18).TRPV4 was identified originally as a channel activated by hypotonic cell swelling (11,13,19), but later reports show that it can be activated also by synthetic agonists, such as the phorbol ester 4␣-phorbol 12,13-didecanoate (4␣-PDD) (5), temperatures Ͼ27°C (6, 20), and acidic pH and citrate (ref. 21; see also ref. 5). Moreover, rec...

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Section: Hypotonicity-induced Activation Of Trpv4 Is Not Mediated By mentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4

Vriens

Watanabe

Janssens

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

571

532

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“…HEK293 cells were transiently transfected with the pCINeo/IRES-GFP/ rbECaC vector using previously described methods (15).…”

Section: Methodsmentioning

confidence: 99%

Heat-evoked Activation of TRPV4 Channels in a HEK293 Cell Expression System and in Native Mouse Aorta Endothelial Cells

Watanabe

Vriens

Suh

et al. 2002

Journal of Biological Chemistry

Self Cite

606

457

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We have compared activation by heat of TRPV4 channels, heterogeneously expressed in HEK293 cells, and endogenous channels in mouse aorta endothelium (MAEC). Increasing the temperature above 25°C activated currents and increased [Ca 2؉ ] i in HEK293 cells transfected with TRPV4 and in MAEC. When compared with activation of TRPV4 currents by the selective ligand 4␣PDD (␣-phorbol 12,13-didecanoate), heat-activated currents in both systems showed the typical biophysical properties of currents through TRPV4, including their single channel conductance. Deletion of the three N-terminal ankyrin binding domains of TRPV4 abolished current activation cells by heat in HEK293. In inside-out patches, TRPV4 could not be activated by heat but still responded to the ligand 4␣PDD. In MAEC, the same channel is activated under identical conditions as in the HEK expression system. Our data indicate that TRPV4 is a functional temperature-sensing channel in native endothelium, that is likely involved in temperature-dependent Ca 2؉ signaling. The failure to activate TRPV4 channels by heat in inside-out patches, which responded to 4␣PDD, may indicate that heat activation depends on the presence of an endogenous ligand, which is missing in inside-out patches.Sensing of temperature in the body and the environment is one of the most essential mechanisms for controlling the homeostasis of several regulatory pathways in the mammalian body (1). In recent years, unraveling of thermosensing mechanisms has been very successful, because at least four members of the TRPV subfamily of transient receptor potential cation channels, TRPV 1 1, -2, -3, and -4 and a more distantly related protein TRPM8 have been identified (for a unified nomenclature see Refs. 2 and 3) as sensors of temperature. Proteins of this subfamily typically contain 3-6 ankyrin repeats in the N terminus, and six transmembrane segments with a pore region between segments 5 and 6. The first identified non-mammalian member of this subfamily, the Caenorhabditis elegans OSM-9 channel, is activated by changes in osmolarity (4). The second protein of the TRPV family that has been identified is the mammalian vanilloid receptor channel VR1 (TRPV1), which is activated by vanilloid compounds such as capsaicin, pepper, hot chili, moderate heat, or protons (5). Unlike TRPV1, another close relative of this channel, TRPV2, is constitutively activated by growth factors (6) or by noxious heat (7). TRPV1 and TRPV2 are activated by temperatures above 43 and 52°C, respectively (5, 7). Currents through TRPV3 exponentially increase at temperatures above 35°C (8 -10). It has also been shown in current measurements on oocytes and by cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i) measurements in HEK cells that TRPV4 is activated in both expression systems at temperature above 30°C (11). TRPM8 is activated by temperatures below 22°C and is therefore a candidate for cold reception (12, 13).So far, the molecular mechanism of channel activation by heat for any of these channels is not known, and functional measurements of ...

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TRPChannels

Gees

Owsianik

Nilius

et al. 2012

Comprehensive Physiology

149

120

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TRP channels constitute a large superfamily of cation channel forming proteins, all related to the gene product of the transient receptor potential (trp) locus in Drosophila. In mammals, 28 different TRP channel genes have been identified, which exhibit a large variety of functional properties and play diverse cellular and physiological roles. In this article, we provide a brief and systematic summary of expression, function, and (patho)physiological role of the mammalian TRP channels.

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Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells

Cited by 127 publications

References 26 publications

Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4

Cell swelling, heat, and chemical agonists use distinct pathways for the activation of the cation channel TRPV4

Heat-evoked Activation of TRPV4 Channels in a HEK293 Cell Expression System and in Native Mouse Aorta Endothelial Cells

TRPChannels

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