Structural Basis of Temperature Sensation by the TRP Channel TRPV3

Singh, Appu Kumar; McGoldrick, L.L.; Demirkhanyan, Lusine; Leslie, Merfilius; Zakharian, Eleonora; Sobolevsky, Alexander I.

doi:10.1016/j.bpj.2019.11.302

Cited by 19 publications

(66 citation statements)

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“…14). Recent TRPV3 structural studies that capture the putative temperature-dependent conformational changes, indicate that the S4 3 10 -helix converts to an α-helix with a mutant that reflects the putative temperature-activated state 78 , similar to what our temperature-dependent studies indicate. This TRPV3 structural study also implicates changes in solvent exposure to the S1-S2 loop that causes distortions in S1, S2, and S3 helices.…”

Section: Discussionsupporting

confidence: 83%

“…The residue equivalent to Y554 in TRPV3 is Y564 ( Supplementary Fig. 15) and functional characterization of TRPV3 Y564A shows that this channel is highly sensitized relative to the WT TRPV3 and reduces thermosensitivity, as estimated from the reported Q 10 values, from a ΔH of~65 kcal mol −1 for the WT channel to~4 kcal mol −1 for the Y564A mutant 78 . Taken together the TRPV1, V3, and V4 data suggest that R557 in TRPV1 functions as a switch, which couples both heat and ligand stimuli (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing

et al. 2020

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Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a wellstudied heat-sensing receptor that is also activated by vanilloid compounds, including capsaicin. Despite significant interest, the molecular underpinnings of thermosensing have remained elusive. The TRPV1 S1-S4 membrane domain couples chemical ligand binding to the pore domain during channel gating. Here we show that the S1-S4 domain also significantly contributes to thermosensing and couples to heat-activated gating. Evaluation of the isolated human TRPV1 S1-S4 domain by solution NMR, far-UV CD, and intrinsic fluorescence shows that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity. Further NMR characterization of the temperature-dependent conformational changes suggests the contribution of the S1-S4 domain to thermosensing shares features with known coupling mechanisms between this domain with ligand and pH activation. Taken together, this study shows that the TRPV1 S1-S4 domain contributes to TRPV1 temperature-dependent activation.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing

et al. 2020

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“…From a molecular perspective, amino acids at or close to the HLH domain have been implicated in the modulation of temperature-activation in other members of the TRPV family such as TRPV1 and TRPV3 [40][41][42] , and chemical-activation in TRPA1 43 . Molecular dynamic simulations performed on TRPV1 channels suggested that the HLH domain interacts with the intracellular linkers S2-S3 and S4-S5 during gating 44 .…”

Section: Discussionmentioning

confidence: 99%

Evolutionary analyses reveal independent origins of gene repertoires and structural motifs associated to fast inactivation in calcium-selective TRPV channels

Flores-Aldama

Vandewege

Zavala

et al. 2020

Sci Rep

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Essential for calcium homeostasis, TRPV5 and TRPV6 are calcium-selective channels belonging to the transient receptor potential (TRP) gene family. In this study, we investigated the evolutionary history of these channels to add an evolutionary context to the already available physiological information. Phylogenetic analyses revealed that paralogs found in mammals, sauropsids, amphibians, and chondrichthyes, are the product of independent duplication events in the ancestor of each group. Within amniotes, we identified a traceable signature of three amino acids located at the amino-terminal intracellular region. The signature correlates with both the duplication events and the phenotype of fast inactivation observed in mammalian TRPV6 channels. Electrophysiological recordings and mutagenesis revealed that the signature sequence modulates the phenotype of fast inactivation in all clades of vertebrates but reptiles. A transcriptome analysis showed a change in tissue expression from gills, in marine vertebrates, to kidneys in terrestrial vertebrates. Our results highlight a cytoplasmatic structural triad composed by the Helix-Loop-Helix domain, the S2-S3 linker, and the TRP domain helix that is important on modulating the activity of calcium-selective TRPV channels. In vertebrates, epithelial calcium absorption is a crucial physiological process needed to maintain Ca 2+ homeostasis. Epithelia consist of a continuous layer of individual cells where calcium absorption is maintained by two routes, the transcellular and paracellular pathways 1,2. Tight junctions regulate the passive passage of ions and molecules through the paracellular pathway 2. Calcium permeation through this pathway constitutes a major route for Ca 2+ absorption under normal physiological conditions 1. On the other hand, the transcellular pathway implicates controlled Ca 2+ movement through epithelial barriers and occurs against a concentration gradient in normal conditions. It is an active and saturable process, maintained by an array of transporters, pumps, and ion channels 1. TRPV5 and TRPV6 are calcium-selective ion channel members of the Transient Receptor Potential (TRP) gene family 3. These proteins, expressed at the apical membrane of Ca 2+ transporting epithelia, serve as entry channels in transepithelial Ca 2+ transport 3. In agreement with their physiological role, TRPV6-EphB6 double knockout mice have impaired Ca 2+ homeostasis, evidenced by poor weight gain, decreased bone mineral density, and reduced fertility 4. However, more recent research using TRPV6 null mice suggests that the channel becomes relevant only when dietary calcium supply is low 5. On the other hand, TRPV5 null mice present less severe physiological consequences, nonetheless, the absence of TRPV5 channels causes hypercalciuria, compensatory hyperabsorption of dietary calcium, and abnormal bone thickness 6. At negative membrane potentials, calcium-selective

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“…TRP channels have a notable historical significance in membrane protein structural biology because the structure of TRPV1 determined in 2013 ushered in a new era for solving near-atomic resolution structures of membrane proteins using cryo-electron microscopy (cryo-EM) ( Cao et al, 2013 ; Liao et al, 2013 ). At least one structure has now been reported for each subfamily, with a total of 136 TRP channel structures available at the time we performed this analysis ( Autzen et al, 2018 ; Cao et al, 2013 ; Chen et al, 2017 ; Dang et al, 2019 ; Deng et al, 2018 ; Diver et al, 2019 ; Dosey et al, 2019 ; Duan et al, 2019 ; Duan et al, 2018b ; Duan et al, 2018c ; Fan et al, 2018 ; Grieben et al, 2017 ; Guo et al, 2017 ; Hirschi et al, 2017 ; Huang et al, 2018 ; Hughes et al, 2019 ; Hughes et al, 2018a ; Hughes et al, 2018b ; Hulse et al, 2018 ; Huynh et al, 2016 ; Jin et al, 2017 ; Liao et al, 2013 ; McGoldrick et al, 2019 ; McGoldrick et al, 2018 ; Paulsen et al, 2015 ; Saotome et al, 2016 ; Shen et al, 2016 ; Singh et al, 2019 ; Singh et al, 2018a ; Singh et al, 2018b ; Singh et al, 2018c ; Su et al, 2018a ; Su et al, 2018b ; Tang et al, 2018 ; Vinayagam et al, 2018 ; Wang et al, 2018 ; Wilkes et al, 2017 ; Winkler et al, 2017 ; Yin et al, 2019a ; Yin et al, 2019b ; Yin et al, 2018 ; Zhang et al, 2018 ; Zheng et al, 2018 ; Zhou et al, 2017 ; Zubcevic et al, 2019a ; Zubcevic et al, 2016 ; Zubcevic et al, 2018a ; Zubcevic et al, 2018b ). These structures show that TRP channels are tetramers, with each subunit containing six transmembrane (TM) helices (S...…”

Section: Introductionmentioning

confidence: 99%

Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms

Huffer

Aleksandrova

Jara-Oseguera

et al. 2020

eLife

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The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Comparison of structures determined in the absence or presence of activating stimuli reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and suggesting that most available structures represent non-conducting states. Comparison of the ion selectivity filters toward the extracellular end of the pore supports existing hypotheses for mechanisms of ion selectivity. Also conserved to varying extents are hot spots for interactions with hydrophobic ligands, lipids and ions, as well as discrete alterations in helix conformations. This analysis therefore provides a framework for investigating the structural basis of TRP channel gating mechanisms and pharmacology, and, despite the large number of structures included, reveals the need for additional structural data and for more functional studies to establish the mechanistic basis of TRP channel function.

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Structural Basis of Temperature Sensation by the TRP Channel TRPV3

Cited by 19 publications

References 0 publications

Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing

Evidence that the TRPV1 S1-S4 membrane domain contributes to thermosensing

Evolutionary analyses reveal independent origins of gene repertoires and structural motifs associated to fast inactivation in calcium-selective TRPV channels

Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms

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