Identification of a Tetramerization Domain in the C Terminus of the Vanilloid Receptor

García-Sanz, Nuria; Fernández-Carvajal, Asia; Morenilla‐Palao, Cruz; Planells-Cases, Rosa; Fajardo-Sánchez, Emmanuel; Fernández‐Ballester, Gregorio; Ferrer‐Montiel, Antonio

doi:10.1523/jneurosci.0202-04.2004

Cited by 176 publications

(156 citation statements)

References 40 publications

(75 reference statements)

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“…The TRP box is a highly conserved hexameric domain in the C-termini of TRP channels, and has been proposed to have a role in subunit multimerization, overall channel gating, and PIP2 binding (1,(36)(37)(38). An R residue in the TRP box of TRPV1 (R701) has been implicated in gating the channel to temperature and chemical stimuli (24,38).…”

Section: R696 Within the Trp Box Is Required For Calcium-dependent 2apbmentioning

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.

102

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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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Section: R696 Within the Trp Box Is Required For Calcium-dependent 2apbmentioning

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.

102

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“…The highly conserved TRP domain, located in the intracellular C-terminus immediately downstream of the S6 transmembrane helix as shown for TRPV1 (Garcia-Sanz et al 2004) 2. The third and fourth ankyrin repeats positioned in Nterminus of TRPV6 (Erler et al 2004) 3.…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

Chubanov

Schnitzler

Wäring

et al. 2005

Naunyn-Schmiedeberg's Arch Pharmacol

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Investigations into Drosophila mutants with impaired vision due to mutations in the transient receptor potential gene (trp) initiated a systematic search for TRP homologs in other species, finally leading to the discovery of a whole new family of plasma membrane cation channels involved in multiple physiological processes. Among the recently discovered TRP cation channels two homologous proteins, TRPM6 and TRPM7, display unique domain compositions and biophysical properties. These remarkable genes are vital for Mg 2+ homeostasis in vertebrates and, if disrupted, lead to cell death or human disease.

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“…To function as nociceptors, TRPV1 subunits must assemble into tetramers (9) as well as be exported to the cell membrane. Previous biochemical and functional investigations of the molecular determinants of TRPV1 assembly have identified the C-terminal tail of the channel as the assembling domain (10,11), yet the exact motif of interaction remains controversial. Although one study found the TRP domain, an ϳ24-residue helix just downstream of the sixth transmembrane region, to promote TRPV1 subunit association (10), another group identified a more distal motif comprising residues 752-772 (termed the tetrameric assembly domain (TAD)) (11).…”

Section: The Trpv1mentioning

confidence: 99%

“…Previous biochemical and functional investigations of the molecular determinants of TRPV1 assembly have identified the C-terminal tail of the channel as the assembling domain (10,11), yet the exact motif of interaction remains controversial. Although one study found the TRP domain, an ϳ24-residue helix just downstream of the sixth transmembrane region, to promote TRPV1 subunit association (10), another group identified a more distal motif comprising residues 752-772 (termed the tetrameric assembly domain (TAD)) (11). The recent release of a high resolution single-particle electron cryomicroscopy (cryo-EM) structure of an assembled TRPV1 channel has highlighted the interactions of a ␤ sheet from one subunit, composed of a C-terminal ␤ strand and two ␤ strands from the N terminus, with the N-terminal ankyrin repeat domain of an adjacent subunit (9).…”

Section: The Trpv1mentioning

confidence: 99%

“…Using the CD4 tag to precipitate complexes, we showed that CD4-Ct interacted with the full-length TRPV1 subunit, a YFP-tagged TRPV1 C terminus, and the 734 -751 and 752-772 fragments but not the 716 -733 region (Fig. 3D) containing part of the TRP-like domain (10). Thus, we have identified two contiguous motifs located in the C-terminal region of TRPV1 that promote channel assembly through interactions with the C termini of adjacent TRPV1 subunits.…”

Section: Detection Of Trpv1 Homomers By Bifc and Bifc/bretmentioning

confidence: 99%

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Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

Flynn

Chapman

Iftinca

et al. 2014

Journal of Biological Chemistry

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Background: Assembly of TRPV1 subunits forms functional channels that transduce noxious stimuli. Results: We identified a region of the TRPV1 C terminus that mediates subunit assembly and used a disrupting peptide to block association. Conclusion: A short C-terminal motif enables subunit association. Disrupting assembly of TRPV1 subunits attenuates inflammatory hyperalgesia. Significance: TRPV1 subunit association could be targeted for pain relief.

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Identification of a Tetramerization Domain in the C Terminus of the Vanilloid Receptor

Cited by 176 publications

References 40 publications

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

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

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

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