Dual regulation of TRPV1 channels by phosphatidylinositol via functionally distinct binding sites

Yazici, Aysenur; Gianti, Eleonora; Kasimova, Marina A.; Lee, Bo Hyun; Carnevale, Vincenzo; Rohács, Tibor

doi:10.1016/j.jbc.2021.100573

Cited by 17 publications

(26 citation statements)

References 47 publications

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“…The striking overlap between PI and RTX in this site suggests the possibility that PI is an antagonist of vanilloids in TRPV1. Indeed, a recent study showed that PI inhibits TRPV1 in excised inside-out patches, and that inhibition is the strongest at low capsaicin concentrations and lost at high capsaicin concentration, suggesting that PI competitively inhibits capsaicin activation of TRPV1 (Yazici et al, 2021). A similar example of overlapping lipid-drug binding modes was also observed in TRPA1 structures in complex with the agonist, GNE551 (Suo et al, 2020;Liu et al, 2021; Figure 7B).…”

Section: Vanilloid Binding Sitesupporting

confidence: 55%

“…Most TRP channels are regulated by PIP 2 , a major phosphoinositide in the plasma membrane inner leaflet. Both positive and negative regulatory effects of PIP 2 have been reported in TRPV1 and other TRP channels, and there is evidence to suggest that multiple distinct binding sites account for these varied effects (Yazici et al, 2021). While phosphoinositides, such as PI antagonize TRPV1 activation by competing for vanilloid agonist binding, another site(s) likely mediates PIP 2 activation of TRPV1.…”

Section: Pip 2 and Other Lipid Binding Sitesmentioning

confidence: 99%

“…While phosphoinositides, such as PI antagonize TRPV1 activation by competing for vanilloid agonist binding, another site(s) likely mediates PIP 2 activation of TRPV1. Molecular docking and MD simulations identified a putative PIP 2 binding site in TRPV1, adjacent to the vanilloid binding site, where the headgroup is interacting with basic residues in the S4-S5 linker and TRP domain (Poblete et al, 2015;Yazici et al, 2021). Mutations of these residues significantly right-shift the PIP 2 dose-response curve (Poblete et al, 2015).…”

Section: Pip 2 and Other Lipid Binding Sitesmentioning

confidence: 99%

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Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

2022

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Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches.

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Section: Vanilloid Binding Sitesupporting

confidence: 55%

Section: Pip 2 and Other Lipid Binding Sitesmentioning

confidence: 99%

Section: Pip 2 and Other Lipid Binding Sitesmentioning

confidence: 99%

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Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

2022

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“…Such interaction cannot be explained by direct contact between TM2 and TDh. Thus, it would not be unreasonable to suggest that this interaction between TM2 and the TDh involves an additional linker molecule such as PIP 2 or other lipid binding to this region (Poblete et al, 2014; Yin et al, 2017; Yazici et al, 2021; Hughes et al, 2018)). Interactions between the channel and the membrane at the cytosol-membrane interface is emerging as a common theme in TRPs.…”

Section: Resultsmentioning

confidence: 99%

Sequence conservation and structural features that are common within TRP channels

Cabezas-Bratesco

Colenso

Zavala

et al. 2021

Preprint

Self Cite

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TRP proteins are a large family of cation selective channels, surpassed in variety only by voltage-gated potassium channels. Detailed molecular mechanisms governing how membrane voltage, ligand binding, or temperature can induce conformational changes promoting the open state of the channel are still missing for TRP channels. Aiming to unveil distinctive structural features common to the transmembrane domains within the TRP family, we performed bioinformatic analyses over a large set of TRP channel genes. Here we report a discrete and exceptionally conserved set of residues. This fingerprint is composed of eleven residues localized at equivalent three-dimensional positions in TRP channels from the different subtypes. Moreover, these amino acids are arranged in three groups, connected by a set of aromatics located at the core of the transmembrane structure. We hypothesize that differences in the connectivity between these different groups of residues harbors the apparent differences in coupling strategies used by TRP subgroups.

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“…To the best of our knowledge, molecular docking and MD simulations have not been applied yet to study the binding of photoswitchable lipids to TRP channels. However, these two computational techniques have been extensively used to investigate channel modulation by other TRP ligands [ 58 , 59 , 60 , 61 , 62 ] and thus their use could be easily extended to photopharmacological applications.…”

Section: Computational Modeling Of Photoswitchable Ligands Targeting Voltage-gated Ion Channelsmentioning

confidence: 99%

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.

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Dual regulation of TRPV1 channels by phosphatidylinositol via functionally distinct binding sites

Cited by 17 publications

References 47 publications

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Sequence conservation and structural features that are common within TRP channels

Photopharmacology of Ion Channels through the Light of the Computational Microscope

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