scholarly journals The Structural Basis of Calcium-Dependent Inactivation of the Transient Receptor Potential Vanilloid 5 Channel

Biochemistry ◽  
2018 ◽  
Vol 57 (18) ◽  
pp. 2623-2635 ◽  
Author(s):  
Fedir M. Bokhovchuk ◽  
Neil Bate ◽  
Nadezda V. Kovalevskaya ◽  
Benjamin T. Goult ◽  
Chris A. E. M. Spronk ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Structural Basis ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Dependent ◽  
Dependent Inactivation ◽  
Transient Receptor

scholarly journals Pore Helix Domain Is Critical to Camphor Sensitivity of Transient Receptor Potential Vanilloid 1 Channel

2012 ◽  
Vol 116 (4) ◽  
pp. 903-917 ◽  
Author(s):  
Lenka Marsakova ◽  
Filip Touska ◽  
Jan Krusek ◽  
Viktorie Vlachova
Keyword(s):  
Spatial Distribution ◽  
Plasma Membranes ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Structural Basis ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channel ◽  
Patch Clamp Technique ◽  
Trpv1 Channels ◽  
Transient Receptor

Background The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new research paths toward understanding why this naturally occurring monoterpene is widely used in human medicine for its local counter-irritant, antipruritic, and anesthetic properties. However, the molecular basis for camphor sensitivity remains mostly unknown. The authors attempt to explore the nature of the activation pathways evoked by camphor and narrow down a putative interaction site at TRPV1. Methods The authors transiently expressed wild-type or specifically mutated recombinant TRPV1 channels in human embryonic kidney cells HEK293T and recorded cation currents with the whole cell, patch clamp technique. To monitor changes in the spatial distribution of phosphatidylinositol 4,5-bisphosphate, they used fluorescence resonance energy transfer measurements from cells transfected with the fluorescent protein-tagged pleckstrin homology domains of phospholipase C. Results The results revealed that camphor modulates TRPV1 channel through the outer pore helix domain by affecting its overall gating equilibrium. In addition, camphor, which generally is known to decrease the fluidity of cell plasma membranes, may also regulate the activity of TRPV1 by inducing changes in the spatial distribution of phosphatidylinositol-4,5-bisphosphate on the inner leaflet of the plasma membrane. Conclusions The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.

scholarly journals Structural insight into TRPV5 channel function and modulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8869-8878 ◽  
Author(s):  
Shangyu Dang ◽  
Mark K. van Goor ◽  
Daniel Asarnow ◽  
YongQiang Wang ◽  
David Julius ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Resolution Electron ◽  
Trpv Channels ◽  
Transient Receptor ◽  
Lipid Nanodiscs ◽  
Insight Into

TRPV5 (transient receptor potential vanilloid 5) is a unique calcium-selective TRP channel essential for calcium homeostasis. Unlike other TRPV channels, TRPV5 and its close homolog, TRPV6, do not exhibit thermosensitivity or ligand-dependent activation but are constitutively open at physiological membrane potentials and modulated by calmodulin (CaM) in a calcium-dependent manner. Here we report high-resolution electron cryomicroscopy structures of truncated and full-length TRPV5 in lipid nanodiscs, as well as of a TRPV5 W583A mutant and TRPV5 in complex with CaM. These structures highlight the mechanism of calcium regulation and reveal a flexible stoichiometry of CaM binding to TRPV5.

Phosphorylation regulates TRPV1 association with β-arrestin-2

2013 ◽  
Vol 451 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Elaine D. Por ◽  
Ruben Gomez ◽  
Armen N. Akopian ◽  
Nathaniel A. Jeske
Keyword(s):  
Protein Kinase ◽  
Transient Receptor Potential ◽  
Chinese Hamster Ovary Cells ◽  
Critical Role ◽  
Chinese Hamster ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Ovary Cells ◽  
Calcium Dependent ◽  
Transient Receptor

Post-translational modifications in TRPV1 (transient receptor potential vanilloid 1) play a critical role in channel activity. Phosphorylation of serine/threonine residues within the N- and C-termini of TRPV1 are implicated in receptor sensitization and activation. Conversely, TRPV1 desensitization occurs via a calcium-dependent mechanism and leads to receptor de-phosphorylation. Importantly, we recently demonstrated that TRPV1 association with β-arrestin-2 is critical to receptor desensitization via its ability to scaffold the phosphodiesterase PDE4D5 to the receptor, regulating TRPV1 phosphorylation. In the present study, we demonstrate that phosphorylation of TRPV1 and β-arrestin-2 regulates this association at the membrane. Under serum-free media conditions, we observed a significant decrease in TRPV1 and β-arrestin-2 association in transfected CHO (Chinese-hamster ovary) cells. Pharmacological activation of the kinases PKA (protein kinase A) and PKC (protein kinase C) led to a robust increase in TRPV1 and β-arrestin-2 association, whereas inhibition of PKA and PKC decreased association. Previously, we identified potential PKA residues (Ser116, Thr370) in the N-terminus of TRPV1 modulated by β-arrestin-2. In the present study we reveal that the phosphorylation status of Thr370 dictates the β-arrestin-2 and TRPV1 association. Furthermore, we demonstrate that CK2 (casein kinase 2)-mediated phosphorylation of β-arrestin-2 at Thr382 is critical for its association with TRPV1. Taken together, the findings of the present study suggest that phosphorylation controls the association of TRPV1 with β-arrestin-2.

scholarly journals Structural insight into TRPV5 channel function and modulation

2018 ◽  
Author(s):  
Shangyu Dang ◽  
Mark K. van Goor ◽  
YongQiang Wang ◽  
David Julius ◽  
Yifan Cheng ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Complex Structure ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Calcium Dependent ◽  
Resolution Electron ◽  
Trpv Channels ◽  
Structural Insight ◽  
Transient Receptor ◽  
Insight Into

AbstractTRPV5 (transient receptor potential vanilloid) is a unique calcium-selective TRP channel that is essential for calcium homeostasis. TRPV5 and its close homologue TRPV6 do not exhibit thermosensitivity or ligand-dependent activation, unlike other TRPV channels, but are constitutively opened at physiological membrane potentials. Here, we report high resolution electron cryo-microscopy (cryo-EM) structures of truncated and full length TRPV5 in lipid nanodisc, as well as a TRPV5 W583A mutant structure and a complex structure of TRPV5 with calmodulin (CaM). These structures highlight and explain functional differences between the thermosensitive and calcium-selective TRPV channels. An extended S1-S2 linker folds on top of the channel that might shield it from modulation by extracellular factors. Resident lipid densities in the homologous vanilloid pocket are different from those previously found in TRPV1, supporting a comparatively more rigid architecture of TRPV5. A ring of tryptophan residues (W583) at the bottom of the pore coordinates a density and mutation of W583 resultes in opening of the lower gate. Moreover, we provide structural insight into the calcium-dependent channel inactivation and propose a flexible stoichiometry for TRPV5 and CaM binding.

scholarly journals A Novel Mechanism for Calmodulin-Dependent Inactivation of Transient Receptor Potential Vanilloid 6

Biochemistry ◽  
2018 ◽  
Vol 57 (18) ◽  
pp. 2611-2622 ◽  
Author(s):  
Neil Bate ◽  
Rachel E. Caves ◽  
Simon P. Skinner ◽  
Benjamin T. Goult ◽  
Jaswir Basran ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Inactivation ◽  
Transient Receptor
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