Molecular Determinants of Permeation through the Cation Channel TRPV4

Voets, Thomas; Prenen, Jean; Vriens, Joris; Watanabe, Hiroyuki; Janssens, Annelies; Wissenbach, Ulrich; Bödding, Matthias; Droogmans, Guy; Nilius, Bernd

doi:10.1074/jbc.m204828200

Cited by 284 publications

(264 citation statements)

References 23 publications

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“…Currents through TRPV4 are outwardly rectifying cation currents characterized by a relative Ca 2ϩ permeability ratio (P Ca ͞P Na ) of Ϸ6 and an Eisenman IV permeation sequence for monovalent cations (5,16). Note that under the patch-clamp conditions used in this study (ruptured patches and strong Ca 2ϩ buffering), little basal-current activity is detected in TRPV4-expressing cells (33).…”

Section: Hypotonicity-induced Activation Of Trpv4 Is Not Mediated Bymentioning

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).…”

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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 Bymentioning

confidence: 99%

mentioning

confidence: 99%

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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“…This result suggests that replacement of an arginine by a lysine at position 696 in the TRP box of TRPV3 drives the channel into a desensitizing state on 2-APB but not camphor stimulation in a calcium-dependent manner. A putative Ca 2ϩ -binding residue in the pore loop domain, aspartate 641, is conserved among all TRPV channels, and is critical to permeation properties of TRP channels (26,27). Mutation of D641 into asparagine (N) has been shown to reduce ruthenium red block and high affinity extracelullar calcium inhibition of TRPV3 and other TRP channels (17,22,26,27).…”

Section: Voltage-dependent Response Remained Intact In 2-apb Mutantsmentioning

confidence: 99%

“…A putative Ca 2ϩ -binding residue in the pore loop domain, aspartate 641, is conserved among all TRPV channels, and is critical to permeation properties of TRP channels (26,27). Mutation of D641 into asparagine (N) has been shown to reduce ruthenium red block and high affinity extracelullar calcium inhibition of TRPV3 and other TRP channels (17,22,26,27). Therefore, we examined whether the D641N mutation could relieve the TRPV3-R696K clone from calcium-dependent loss of 2-APB response.…”

Section: Voltage-dependent Response Remained Intact In 2-apb Mutantsmentioning

confidence: 99%

Two amino acid residues determine 2-APB sensitivity of the ion channels TRPV3 and TRPV4

Grandl

Bandell

et al. 2009

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

103

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Temperature-activated transient receptor potential ion channels (thermoTRPs) are polymodal detectors of various stimuli including temperature, voltage, and chemicals. To date, it is not known how TRP channels integrate the action of such disparate stimuli. Identifying specific residues required for channel-activation by distinct stimuli is necessary for understanding overall TRP channel function. TRPV3 is activated by warm temperatures and various chemicals, and is modulated by voltage. One potent activator of TRPV3 is 2-aminoethyl diphenylborinate (2-APB), a synthetic chemical that modulates many TRP channels. In a high-throughput mutagenesis screen of Ϸ14,000 mutated mouse TRPV3 clones, we found 2 residues (H426 and R696) specifically required for sensitivity of TRPV3 to 2-APB, but not to camphor or voltage. The cytoplasmic N-terminal mutation H426N in human, dog, and frog TRPV3 also effectively abolished 2-APB activation without affecting camphor responses. Interestingly, chicken TRPV3 is weakly sensitive to 2-APB, and the equivalent residue at 426 is an asparagine (N). Mutating this residue to histidine induced 2-APB sensitivity of chicken TRPV3 to levels comparable for other TRPV3 orthologs. The cytoplasmic C-terminal mutation R696K in the TRP box displayed 2-APB specific deficits only in the presence of extracellular calcium, suggesting involvement in gating. TRPV4, a related thermoTRP, is 2-APB insensitive and has variant sequences at both residues identified here. Remarkably, mutating these 2 residues in TRPV4 to TRPV3 sequences (N426H and W737R) was sufficient to induce TRPV3-like 2-APB sensitivity. Therefore, 2-APB activation of TRPV3 is separable from other activation mechanisms, and depends on 2 cytoplasmic residues.A subset of transient receptor potential (TRP) ion channels have important roles in sensory biology, including pain and thermosensation (1-4). The requirement of several so-called thermoTRPs in thermosensation in vivo has been demonstrated, suggesting that these ion channels have a physiological role as molecular thermometers (5-9). Thresholds of temperatureactivation of thermoTRPs are shifted in the presence of chemical agonists, effectively modulating thermosensation (1, 10-12). Several natural and synthetic compounds have been identified as agonists or antagonists for each of the thermoTRPs (13). However, little is known about how these chemicals modulate TRP channel activity.TRPV3, one of these thermoTRPs, is a nonselective cation channel expressed primarily in mammalian keratinocytes, and is involved in thermosensation (4,7,14). Like other thermoTRP channels, TRPV3 is a polymodal detector of temperature (heat) and chemicals. TRPV3 agonists include structurally-related natural compounds such as camphor, thymol, and carvacrol (15, 16). One of the most potent TRPV3 agonists is 2-aminoethyl diphenylborinate (2-APB), a synthetic compound that modulates the activity of many ion channels. It is a common activator of the heat-gated TRPV ion-channels TRPV1, TRPV2, and TRPV3 (17,18). Besides i...

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“…The general topology of a TRP subunit as shown in experimental detail for TRPC channels (Vannier et al 1998) includes intracellular -and C-terminal regions of variable length and six transmembrane spanning domains with a pore loop between transmembrane domain 5 and 6. The localization of the pore loop has been confirmed by mutational analyses of residues within the pore for TRPV5 and TRPV6, TRPV1 and TRPV4 (Garcia-Martinez et al 2000;Nilius et al 2001;Voets et al 2002Voets et al , 2003. In analogy to voltage gated potassium channels it is thought that four subunits need to assemble to form a functional channel.…”

Section: Introductionmentioning

confidence: 91%

Structure-function analysis of TRPV channels

Niemeyer

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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In recent years many new members of the family of TRP ion channels have been identified. These channels are classified into several subgroups and participate in many sensory and physiological functions. TRPV channels are important for the perception of pain, temperature sensing, osmotic regulation, and maintenance of calcium homeostasis, and much recent research concerns the identification of protein domains involved in mediating specific channel functions. Recent literature on TRPV channel subunit composition, protein domains required for subunit assembly, trafficking, and regulation will be reviewed and discussed.

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Molecular Determinants of Permeation through the Cation Channel TRPV4

Cited by 284 publications

References 23 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

Two amino acid residues determine 2-APB sensitivity of the ion channels TRPV3 and TRPV4

Structure-function analysis of TRPV channels

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