The Region Adjacent to the C-end of the Inner Gate in Transient Receptor Potential Melastatin 8 (TRPM8) Channels Plays a Central Role in Allosteric Channel Activation

Taberner, Francisco J.; López-Córdoba, Ainara; Fernández‐Ballester, Gregorio; Korchev, Yuri; Ferrer-Montiel, Antonio

doi:10.1074/jbc.m114.577478

Cited by 31 publications

(51 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structure-function studies pinpoint to the TRP domain as a pivotal region for channel gating and PIP2 modulation as it contains residues central for PIP2 binding [119][120][121][122]. The functional relevance of this domain has been further substantiated by its conformation in the proposed high resolution TRPV1 structural model [11].…”

Section: Modulation Of Trp Channel Function By Phosphoinositidesmentioning

confidence: 96%

“…Interestingly, the W697 is interacting with S4-S5 loop considered central for voltage sensing [11,121]. In TRPM8, mutations Y981E and Y981K destabilized the gate resulting in constitutive channel opening [122]. Interestingly, subsequent mutations on the S6-TRP box linker restored the regulated activity mainly by reestablishing coupling of stimuli sensing and pore opening.…”

Section: Modulation Of Trp Channel Function By Phosphoinositidesmentioning

confidence: 97%

See 1 more Smart Citation

TRP channels interaction with lipids and its implications in disease

Taberner

Fernández‐Ballester

Fernández-Carvajal

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

View full text Add to dashboard Cite

Transient receptor potential (TRP) proteins are a family of ion channels central for sensory signaling. These receptors and, in particular, those involved in thermal sensing are also involved in pain signaling. Noteworthy, thermosensory receptors are polymodal ion channels that respond to both physical and chemical stimuli, thus integrating different environmental clues. In addition, their activity is modulated by algesic agents and lipidergic substances that are primarily released in pathological states. Lipids and lipid-like molecules have been found that can directly activate some thermosensory channels or modulate their activity by either potentiating or inhibiting it. To date, more than 50 endogenous lipids that can regulate TRP channel activity in sensory neurons have been described, thus representing the majority of known endogenous TRP channel modulators. Lipid modulators of TRP channels comprise lipids from a variety of metabolic pathways, including metabolites of the cyclooxygenase, lipoxygenase and cytochrome-P450 pathways, phospholipids and lysophospholipids. Therefore, TRP-channels are able to integrate and interpret incoming signals from the different metabolic lipid pathways. Taken together, the large number of lipids that can activate, sensitize or inhibit neuronal TRP-channels highlights the pivotal role of these molecules in sensory biology as well as in pain transduction and perception. This article is part of a Special Issue entitled: Lipid-protein interactions. Guest Editors: Amitabha Chattopadhyay and Jean-Marie Ruysschaert.

show abstract

Section: Modulation Of Trp Channel Function By Phosphoinositidesmentioning

confidence: 96%

Section: Modulation Of Trp Channel Function By Phosphoinositidesmentioning

confidence: 97%

TRP channels interaction with lipids and its implications in disease

Taberner

Fernández‐Ballester

Fernández-Carvajal

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

Self Cite

View full text Add to dashboard Cite

show abstract

“…34 As shown by their homology models based on the experimentally solved structures of TRPV1, the conformational changes in the voltage sensors by activating stimuli could be associated to a widening of the S6 C-end, which in turn might disrupts the intersubunit interactions in the region of Tyr981, thus favoring channel opening. 35 We ran a series of simulations to investigate whether a TRPM8 monomer was able to bind the newly-synthesized small molecules and to test the influence of this binding on the conformation of the functional 980-992 region.…”

Section: Molecular Modeling and Structural Rationalementioning

confidence: 99%

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

et al. 2016

Self Cite

View full text Add to dashboard Cite

Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach mainly for the treatment of pain. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. As a result of a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, compound 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, compound 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 = 367±24 nM). Molecular modelling studies using a homology model of a single TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing two different binding modes for the agonist and the antagonist.

show abstract

“…For TRPM8, we selected variants representing four non-conservative substitutions located in two evolutionarily conserved sections of the N-terminal domain. Structure-function studies for TRPM8 have focused mainly on amino acid residues in the transmembrane bundle [5,[13][14][15][16][17][18][19] rather than the N-terminal domain [20], although a potential structure for the latter has been proposed as part of a whole molecule model [21].…”

Section: Introductionmentioning

confidence: 99%

Genetic variants affecting human TRPA1 or TRPM8 structure can be classified in vitro as ‘well expressed’, ‘poorly expressed’ or ‘salvageable’

2015

View full text Add to dashboard Cite

SynopsisMultiple mis-sense variants of TRPA1 (transient receptor potential A1) and TRPM8 (transient receptor potential M8) are recorded in the human genome single nt polymorphism (SNP) database, but their potential impact on channel signalling in patho-physiology is not fully explored. Variants, mostly quite rare in the general human population, alter sites in different structural domains of these homo-tetrameric ion channel proteins. The effects of individual SNPs affecting the large cytoplasmic N-terminal domain have not been completely documented for TRPM8 or TRPA1. We examined the Ca 2 + signalling properties of a short-list of eight variants affecting the N-terminal domain by individual expression in human embryonic kidney HEK293 or neuroblastoma (SH-SY5Y) cell lines (four SNP variants for TRPM8: G150R, K423N, R475C, R485W and four for TRPA1: Y69C, A366D, E477K, D573A). These were compared with TRPA1 SNP variants affecting intracellular loops located beyond the N-terminal domain and associated with gain of function (such as increased sensitivity to agonists: TRPA1 R797T and N855S). A substitution in TRPA1 (Y69C) exhibited high expression/sensitivity to agonists (high iCa 2 + max (maximum level of intracellular calcium ion), similar to R797T, but less sensitive than N855S), whereas each of the other non-conservative substitutions exhibited poor signalling response (low iCa 2 + max). Responses from these poorly expressed variants could be salvaged, to different extents, by pre-treating cells with the Src (Src protein) family inhibitor protein kinase inhibitor PP2 (PP2: 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo [3,4-d]pyrimidine, 4-Amino-5-(4-chlorophenyl)-7-(tbutyl)pyrazolo [3,4-d]pyrimidine), or with micromolar Zn 2 + . The TRPA1 variants and several experimental mutants (TRPA1 Y97F, Y226F and YY654-655FF) expressed poorly in SH-SY5Y compared with HEK293 cells. More in-depth studies are needed to identify SNP variants eliciting gain of function in these TRP (transient receptor potential) channels and to assess their roles in medical conditions.

show abstract

The Region Adjacent to the C-end of the Inner Gate in Transient Receptor Potential Melastatin 8 (TRPM8) Channels Plays a Central Role in Allosteric Channel Activation

Cited by 31 publications

References 38 publications

TRP channels interaction with lipids and its implications in disease

TRP channels interaction with lipids and its implications in disease

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Genetic variants affecting human TRPA1 or TRPM8 structure can be classified in vitro as ‘well expressed’, ‘poorly expressed’ or ‘salvageable’

Contact Info

Product

Resources

About