TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site

Nadezhdin, Kirill D.; Neuberger, Arthur; Khosrof, Lena S.; Talyzina, Irina A.; Khau, Jeffrey; Yelshanskaya, Maria V.; Sobolevsky, Alexander I.

doi:10.1126/sciadv.adn2453

Cited by 10 publications

(3 citation statements)

References 55 publications

(107 reference statements)

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“…The proposed classification of TRPV channel pore states fully agrees with the earlier described model of TRPV3 gating 15 , 28 – 30 , which follows the α-closed→π-closed→π-open transition. We show that the most energetically preferable and, as a result, the most structurally stable conformation of the TRPV channel gate is the closed state with entirely α-helical S6 (α-closed).…”

Section: Discussionsupporting

confidence: 85%

“…Interestingly, the gating trigger described above is not the only one found in TRPV channels. Lipid molecules bound to the surface of TRPV3 in the closed state were shown to dissociate from the channel and act as a gating trigger upon channel opening 15 , 18 , 28 . Thus, the TRPV channel function is regulated by at least two “fuses” – the protein itself and the annular lipids.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels

Trofimov,

Krylov,

Minakov

et al. 2024

Commun Chem

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Structural biology is solving an ever-increasing number of snapshots of ion channel conformational ensembles. Deciphering ion channel mechanisms, however, requires understanding the ensemble dynamics beyond the static structures. Here, we present a molecular modeling-based approach characterizing the ion channel structural intermediates, or their “dynamic molecular portraits”, by assessing water and ion conductivity along with the detailed evaluation of pore hydrophobicity and residue packing. We illustrate the power of this approach by analyzing structures of few vanilloid-subfamily transient receptor potential (TRPV) channels. Based on the pore architecture, there are three major states that are common for TRPVs, which we call α-closed, π-closed, and π-open. We show that the pore hydrophobicity and residue packing for the open state is most favorable for the pore conductance. On the contrary, the α-closed state is the most hydrophobic and always non-conducting. Our approach can also be used for structural and functional classification of ion channels.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels

Trofimov,

Krylov,

Minakov

et al. 2024

Commun Chem

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“…The action of ddA was irreversible in vitro; however, it is unlikely to be covalent, as the inhibition was partial and selective to TRPV3. We suggest that ddA converts TRPV3 into an inactivated, or desensitized, state that was structurally characterized recently, although we did not observe the activation of TRPV3 by ddA, which makes us designate the mode of action as “inhibition”. A mode of action, when a ligand effectively desensitizes TRPV3 to further activations, was earlier observed for cannabinoids …”

Section: Discussionmentioning

confidence: 99%

A Diterpenoid of the Medicinal Plant Andrographis paniculata Targets Cutaneous TRPV3 Channel and Relieves Itch

Kalinovskii,

Logashina,

Palikova

et al. 2024

J. Nat. Prod.

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Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel implicated in skin physiology and itch. TRPV3 inhibitors can present a novel strategy for combating debilitating itch conditions, and medicinal plants are a natural pool of such compounds. Here, we report the isolation of a TRPV3inhibiting compound from Andrographis paniculata, a medicinal plant with anti-inflammatory properties whose bioactive components are poorly characterized in terms of molecular targets. Using 1 H and 13 C NMR and high-resolution mass spectrometry, the compound was identified as a labdane-type diterpenoid, 14-deoxy-11,12-didehydroandrographolide (ddA). The activity of the compound was evaluated by fluorescent calcium assay and manual whole-cell patch-clamp technique. ddA inhibited human TRPV3 in stably expressing CHO and HaCaT keratinocytes, acting selectively among other TRP channels implicated in itch and inflammation and not showing toxicity to HaCaT cells. Antipruritic effects of the compound were evaluated in scratching behavior models on ICR mice. ddA suppressed itch induced by the TRPV3 activator carvacrol. Additionally, ddA potently suppressed histamine-induced itch with efficacy comparable to loratadine, a clinically used antihistamine drug. These results suggest the potential of ddA as a possible safe and efficacious alternative for antipruritic therapy.

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Thermoring basis for heat unfolding‐induced inactivation in TRPV1

Wang

2024

Natural Sciences

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Transient receptor potential vanilloid‐1 (TRPV1) is a capsaicin receptor that employs use‐dependent desensitization to protect highly evolved mammals from noxious heat damage in response to repeated or constant heat stimuli. However, the underlying structural factor or motif has not been precisely resolved. In this computational study, the graph theory‐based grid thermodynamic model was used to reveal how temperature‐dependent noncovalent interactions, as identified in the 3D structures of rat TRPV1, could develop a well‐organized fluidic grid‐like mesh network. This network features various topological grids constrained as thermosensitive rings that range in size from the biggest to the smallest, governing distinct structural and functional traits of the channel in response to different temperature degrees. After discovering that heat unfolding of three specific biggest grids, one in the closed state and two in the open state, respectively, causes the reversible activation at 43°C and thermal inactivation between 56°C and 61°C, a smaller random grid was also found to be responsible for irreversible inactivation and use‐dependent desensitization from the pre‐open closed state within the temperature range of 43°C–61°C. Thus, these two distinct inactivation pathways of TRPV1 may be involved in protecting those mammals against noxious heat damage.Key Points A perturbation at the protein–water interface was accompanied by partial heat or cold unfolding of the membrane protein. A reversible or irreversible gating transition of an ion channel may result from a specific or random interaction between two active sites, respectively. Kinetically driven protein aggregation was not the cause of thermodynamically trapped irreversible inactivation, but rather a later stage of partial heat‐induced unfolding.

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TRPV3 activation by different agonists accompanied by lipid dissociation from the vanilloid site

Cited by 10 publications

References 55 publications

Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels

Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels

A Diterpenoid of the Medicinal Plant Andrographis paniculata Targets Cutaneous TRPV3 Channel and Relieves Itch

Thermoring basis for heat unfolding‐induced inactivation in TRPV1

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