scholarly journals Structure of full-length human TRPM4

2018 ◽  
Vol 115 (10) ◽  
pp. 2377-2382 ◽  
Author(s):  
Jingjing Duan ◽  
Zongli Li ◽  
Jian Li ◽  
Ana Santa-Cruz ◽  
Silvia Sanchez-Martinez ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Coiled Coil ◽  
Receptor Potential ◽  
Lipid Binding ◽  
Full Length ◽  
Intramolecular Interactions ◽  
Coiled Coil Domain ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na+-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4.

scholarly journals Structural insights into TRPM8 inhibition and desensitization

Science ◽  
2019 ◽  
Vol 365 (6460) ◽  
pp. 1434-1440 ◽  
Author(s):  
Melinda M. Diver ◽  
Yifan Cheng ◽  
David Julius
Keyword(s):  
Conformational Changes ◽  
Calcium Binding ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Chemical Structures ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Large Rearrangements

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo–electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

scholarly journals Molecular mechanism of TRPV2 channel modulation by cannabidiol

2019 ◽  
Author(s):  
Ruth A. Pumroy ◽  
Amrita Samanta ◽  
Yuhang Liu ◽  
Taylor E.T. Hughes ◽  
Siyuan Zhao ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Cannabis Sativa ◽  
Trp Channels ◽  
Critical Role ◽  
Channel Gating ◽  
Receptor Potential ◽  
Lipid Binding ◽  
Transient Receptor Potential Vanilloid ◽  
Structure Based Drug Design ◽  
Transient Receptor

SUMMARYTransient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is a potent activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length TRPV2 channel in a CBD-bound state in detergent and in PI(4,5)P2 enriched nanodiscs by cryo-electron microscopy. CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. Comparison between apo- and two CBD-bound TRPV2 structures reveals that the S4-S5 linker plays a critical role in channel gating upon CBD binding. The TRPV2 “vanilloid” pocket, which is critical for ligand-dependent gating in other TRPV channels, stays unoccupied by annular lipids, PI(4,5)P2, or CBD. Together these results provide a foundation to further understand TRPV channel gating properties and their divergent physiological functions and to accelerate structure-based drug design.

scholarly journals Structure of the ancestral TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium

2020 ◽  
Author(s):  
Tofayel Ahmed ◽  
Collin R. Nisler ◽  
Edwin C. Fluck ◽  
Marcos Sotomayor ◽  
Vera Y. Moiseenkova-Bell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Trp Channels ◽  
Receptor Potential ◽  
Lipid Binding ◽  
Channel Modulation ◽  
Channel Inhibition ◽  
Transient Receptor ◽  
Dynamics Simulations

ABSTRACTTransient Receptor Potential (TRP) channels have evolved in eukaryotes to control various cellular functions in response to a wide variety of chemical and physical stimuli. This large and diverse family of channels emerged in fungi as mechanosensitive osmoregulators. The Saccharomyces cerevisiae vacuolar TRP yeast 1 (TRPY1) is the most studied TRP channel from fungi, but the molecular details of channel modulation remain elusive so far. Here, we describe the full-length cryo-electron microscopy structure of TRPY1 at 3.1 Å resolution. The structure reveals a distinctive architecture for TRPY1 among all eukaryotic TRP channels with an evolutionarily conserved and archetypical transmembrane domain, but distinct structural folds for the cytosolic N- and C-termini. We identified the inhibitory phosphatidylinositol 3-phosphate (PI(3)P) lipid binding site, which sheds light into the lipid modulation of TRPY1 in the vacuolar membrane. The structure also exhibited two Ca2+-binding sites: one in the cytosolic side, implicated in channel activation, and the other in the vacuolar lumen side, involved in channel inhibition. These findings, together with data from molecular dynamics simulations, provide structural insights into the basis of TRPY1 channel modulation by lipids and Ca2+.

scholarly journals Drosophila menthol sensitivity and the Precambrian origins of transient receptor potential-dependent chemosensation

2019 ◽  
Vol 374 (1785) ◽  
pp. 20190369 ◽  
Author(s):  
Nathaniel J. Himmel ◽  
Jamin M. Letcher ◽  
Akira Sakurai ◽  
Thomas R. Gray ◽  
Maggie N. Benson ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Cation Channels ◽  
Transient Receptor Potential Melastatin ◽  
Growing Body ◽  
Sensitivity Studies ◽  
Transient Receptor ◽  
Class Iv

Transient receptor potential (TRP) cation channels are highly conserved, polymodal sensors which respond to a wide variety of stimuli. Perhaps most notably, TRP channels serve critical functions in nociception and pain. A growing body of evidence suggests that transient receptor potential melastatin (TRPM) and transient receptor potential ankyrin (TRPA) thermal and electrophile sensitivities predate the protostome–deuterostome split (greater than 550 Ma). However, TRPM and TRPA channels are also thought to detect modified terpenes (e.g. menthol). Although terpenoids like menthol are thought to be aversive and/or harmful to insects, mechanistic sensitivity studies have been largely restricted to chordates. Furthermore, it is unknown if TRP-menthol sensing is as ancient as thermal and/or electrophile sensitivity. Combining genetic, optical, electrophysiological, behavioural and phylogenetic approaches, we tested the hypothesis that insect TRP channels play a conserved role in menthol sensing. We found that topical application of menthol to Drosophila melanogaster larvae elicits a Trpm - and TrpA1 -dependent nocifensive rolling behaviour, which requires activation of Class IV nociceptor neurons. Further, in characterizing the evolution of TRP channels, we put forth the hypotheses that three previously undescribed TRPM channel clades (basal, αTRPM and βTRPM), as well as TRPs with residues critical for menthol sensing, were present in ancestral bilaterians. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

scholarly journals Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel

2015 ◽  
Vol 146 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Doreen Badheka ◽  
Istvan Borbiro ◽  
Tibor Rohacs
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Kinase Inhibitors ◽  
Trp Channels ◽  
Receptor Potential ◽  
Channel Activity ◽  
Intact Cells ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Phosphatidylinositol 4

Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC8) or natural arachidonyl stearyl (AASt) PI(4,5)P2. The PI(4,5)P2 precursor phosphatidylinositol 4-phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5′-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P2 for activity, our data establish PI(4,5)P2 as a general positive cofactor of this ion channel subfamily.

scholarly journals Molecular mechanism of TRPV2 channel modulation by cannabidiol

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ruth A Pumroy ◽  
Amrita Samanta ◽  
Yuhang Liu ◽  
Taylor ET Hughes ◽  
Siyuan Zhao ◽  
...  
Keyword(s):  
Bound States ◽  
Transient Receptor Potential ◽  
Cannabis Sativa ◽  
Trp Channels ◽  
Critical Role ◽  
Channel Gating ◽  
Receptor Potential ◽  
Lipid Binding ◽  
Transient Receptor Potential Vanilloid ◽  
Transient Receptor

Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV2 channel in apo and CBD-bound states in nanodiscs by cryo-electron microscopy. We show that CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV2 structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV2 apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.

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