Browse
Submit Data
Databases
API
Help

Dataset Information

38 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TRPV1 is activated by both acidic and basic pH.

ABSTRACT: Maintaining physiological pH is required for survival, and exposure to alkaline chemicals such as ammonia (smelling salts) elicits severe pain and inflammation through unknown mechanisms. TRPV1, the capsaicin receptor, is an integrator of noxious stimuli including heat and extracellular acidic pH. Here, we report that ammonia activates TRPV1, TRPA1 (another polymodal nocisensor), and other unknown receptor(s) expressed in sensory neurons. Ammonia and intracellular alkalization activate TRPV1 through a mechanism that involves a cytoplasmic histidine residue, not used by other TRPV1 agonists such as heat, capsaicin or low pH. Our studies show that TRPV1 detects both acidic and basic deviations from homeostatic pH.

SUBMITTER: Dhaka A

PROVIDER: S-EPMC2729567 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

TRPV1 is activated by both acidic and basic pH.

Dhaka Ajay A Uzzell Valerie V Dubin Adrienne E AE Mathur Jayanti J Petrus Matt M Bandell Michael M Patapoutian Ardem A

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090101 1

Maintaining physiological pH is required for survival, and exposure to alkaline chemicals such as ammonia (smelling salts) elicits severe pain and inflammation through unknown mechanisms. TRPV1, the capsaicin receptor, is an integrator of noxious stimuli including heat and extracellular acidic pH. Here, we report that ammonia activates TRPV1, TRPA1 (another polymodal nocisensor), and other unknown receptor(s) expressed in sensory neurons. Ammonia and intracellular alkalization activate TRPV1 thr ...[more]

PMID: 19129393

Similar Datasets

Small molecule positive allosteric modulation of TRPV1 activation by vanilloids and acidic pH.

Project description:Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a high-conductance, nonselective cation channel strongly expressed in nociceptive primary afferent neurons of the peripheral nervous system and functions as a multimodal nociceptor gated by temperatures greater than 43°C, protons, and small-molecule vanilloid ligands such as capsaicin. The ability to respond to heat, low pH, vanilloids, and endovanilloids and altered sensitivity and expression in experimental inflammatory and neuropathic pain models made TRPV1 a major target for the development of novel, nonopioid analgesics and resulted in the discovery of potent antagonists. In human clinical trials, observations of hyperthermia and the potential for thermal damage by suppressing the ability to sense noxious heat suggested that full-scale blockade of TRPV1 function can be counterproductive and subtler pharmacological approaches are necessary. Here we show that the dihydropyridine derivative 4,5-diethyl-3-(2-methoxyethylthio)-2-methyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1477) behaves as a positive allosteric modulator of both proton and vanilloid activation of TRPV1. Under inflammatory-mimetic conditions of low pH (6.0) and protein kinase C phosphorylation, addition of MRS1477 further increased sensitivity of already sensitized TPRV1 toward capsaicin. MRS1477 does not affect inhibition by capsazepine or ruthenium red and remains effective in potentiating activation by pH in the presence of an orthosteric vanilloid antagonist. These results indicate a distinct site on TRPV1 for positive allosteric modulation that may bind endogenous compounds or novel pharmacological agents. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce a selective analgesia through calcium overload restricted to highly active nociceptive nerve endings at sites of tissue damage and inflammation.

| S-EPMC3251023 | biostudies-literature

Biocompatible, pH-sensitive AB(2) Miktoarm Polymer-Based Polymersomes: Preparation, Characterization, and Acidic pH-Activated Nanostructural Transformation.

Project description:Motivated by the limitations of liposomal drug delivery systems, we designed a novel histidine-based AB(2)-miktoarm polymer (mPEG-b-(polyHis)(2)) equipped with a phospholipid-mimic structure, low cytotoxicity, and pH-sensitivity. Using "core-first" click chemistry and ring-opening polymerization, mPEG(2kDa)-b-(polyHis(29kDa))(2) was successfully synthesized with a narrow molecular weight distribution (1.14). In borate buffer (pH 9), the miktoarm polymer self-assembled to form a nano-sized polymersome with a hydrodynamic radius of 70.2 nm and a very narrow size polydispersity (0.05). At 4.2 µmol/mg polymer, mPEG(2kDa)-b-(polyHis(29kDa))(2) strongly buffered against acidification in the endolysosomal pH range and exhibited low cytotoxicity on a 5 d exposure. Below pH 7.4 the polymersome transitioned to cylindrical micelles, spherical micelles, and finally unimers as the pH was decreased. The pH-induced structural transition of mPEG(2kDa)-b-(polyHis(29kDa))(2) nanostructures may be caused by the increasing hydrophilic weight fraction of mPEG(2kDa)-b-(polyHis(29kDa))(2) and can help to disrupt the endosomal membrane through proton buffering and membrane fusion of mPEG(2kDa)-b-(polyHis(29kDa))(2). In addition, a hydrophilic model dye, 5(6)-carboxyfluorescein encapsulated into the aqueous lumen of the polymersome showed a slow, sustained release at pH 7.4 but greatly accelerated release below pH 6.8, indicating a desirable pH sensitivity of the system in the range of endosomal pH. Therefore, this polymersome that is based on a biocompatible histidine-based miktoarm polymer and undergoes acid-induced transformations could serve as a drug delivery vehicle for chemical and biological drugs.

| S-EPMC3447630 | biostudies-literature

Croconaine rotaxane for acid activated photothermal heating and ratiometric photoacoustic imaging of acidic pH.

Project description:Absorption of 808 nm laser light by liposomes containing a pH sensitive, near-infrared croconaine rotaxane dye increases dramatically in weak acid. A stealth liposome composition permits acid activated, photothermal heating and also acts as an effective nanoparticle probe for ratiometric photoacoustic imaging of acidic pH in deep sample locations, including a living mouse.

| S-EPMC4679412 | biostudies-literature

Both basic and acidic amino acid residues of IpTx(a) are involved in triggering substate of RyR1.

Project description:Imperatoxin A (IpTx(a)) is known to modify the gating of skeletal ryanodine receptor (RyR1). In this paper, the ability of charged aa residues of IpTx(a) to induce substate of native RyR1 in HSR was examined. Our results show that the basic residues (e.g., Lys¹?, Lys²?, Lys²², Arg²³, and Arg²?) are important for producing substate of RyR1. In addition, other basic residues (e.g., Lys³?, Arg³¹, and Arg³³ near the C-terminus and some acidic residues (e.g., Glu²?, Asp¹³, and Asp²) are also involved in the generation of substate. Residues such as Lys? and Thr²? may be involved in the self-regulation of substate of RyR1, since alanine substitution of the aa residues led to a drastic conversion to the substate. The modifications of the channel gating by the wild-type and mutant toxins were similar in purified RyR1. Taken together, the specific charge distributions on the surface of IpTx(a) are essential for regulation of the channel gating of RyR1.

| S-EPMC3192407 | biostudies-literature

Identification of acidic extracellular pH-modulated genes

Project description:To investigate the genes that are modulated by acidic extracellular pH, we treated the mouse B16-BL6 cells with acidic medium and then analyzed them comprehensively by cDNA microarray.

2024-09-09 | GSE276124 | GEO

Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity.

Project description:In mammals, many aspects of metabolism are under circadian control. At least in part, this regulation is achieved by core-clock or clock-controlled transcription factors whose abundance and/or activity oscillate during the day. The clock-controlled proline- and acidic amino acid-rich domain basic leucine zipper proteins D-site-binding protein, thyrotroph embryonic factor, and hepatic leukemia factor have previously been shown to participate in the circadian control of xenobiotic detoxification in liver and other peripheral organs. Here we present genetic and biochemical evidence that the three proline- and acidic amino acid-rich basic leucine zipper proteins also play a key role in circadian lipid metabolism by influencing the rhythmic expression and activity of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Our results suggest that, in liver, D-site-binding protein, hepatic leukemia factor, and thyrotroph embryonic factor contribute to the circadian transcription of genes specifying acyl-CoA thioesterases, leading to a cyclic release of fatty acids from thioesters. In turn, the fatty acids act as ligands for PPARα, and the activated PPARα receptor then stimulates the transcription of genes encoding proteins involved in the uptake and/or metabolism of lipids, cholesterol, and glucose metabolism.

| S-EPMC3064322 | biostudies-literature

Proton block of proton-activated TRPV1 current.

Project description:The TRPV1 cation channel is a polymodal nociceptor that is activated by heat and ligands such as capsaicin and is highly sensitive to changes in extracellular pH. In the body core, where temperature is usually stable and capsaicin is normally absent, H(+) released in response to ischemia, tissue injury, or inflammation is the best-known endogenous TRPV1 agonist, activating the channel to mediate pain and vasodilation. Paradoxically, removal of H(+) elicits a transient increase in TRPV1 current that is much larger than the initial H(+)-activated current. We found that this prominent OFF response is caused by rapid recovery from H(+) inhibition of the excitatory current carried by H(+)-activated TRPV1 channels. H(+) inhibited current by interfering with ion permeation. The degree of inhibition is voltage and permeant ion dependent, and it can be affected but not eliminated by mutations to acidic residues within or near the ion selectivity filter. The opposing H(+)-mediated gating and permeation effects produce complex current responses under different cellular conditions that are expected to greatly affect the response of nociceptive neurons and other TRPV1-expressing cells.

| S-EPMC4516785 | biostudies-literature

pH-Lemon, a Fluorescent Protein-Based pH Reporter for Acidic Compartments.

Project description:Distinct subcellular pH levels, especially in lysosomes and endosomes, are essential for the degradation, modification, sorting, accumulation, and secretion of macromolecules. Here, we engineered a novel genetically encoded pH probe by fusing the pH-stable cyan fluorescent protein (FP) variant, mTurquoise2, to the highly pH-sensitive enhanced yellow fluorescent protein, EYFP. This approach yielded a ratiometric biosensor-referred to as pH-Lemon-optimized for live imaging of distinct pH conditions within acidic cellular compartments. Protonation of pH-Lemon under acidic conditions significantly decreases the yellow fluorescence while the cyan fluorescence increases due to reduced Förster resonance energy transfer (FRET) efficiency. Because of its freely reversible and ratiometric responses, pH-Lemon represents a fluorescent biosensor for pH dynamics. pH-Lemon also shows a sizable pH-dependent fluorescence lifetime change that can be used in fluorescence lifetime imaging microscopy as an alternative observation method for the study of pH in acidic cellular compartments. Fusion of pH-Lemon to the protein microtubule-associated protein 1A/1B-light chain 3B (LC3B), a specific marker of autophagic membranes, resulted in its targeting within autolysosomes of HeLa cells. Moreover, fusion of pH-Lemon to a glycophosphatidylinositol (GPI) anchor allowed us to monitor the entire luminal space of the secretory pathway and the exoplasmic leaflet of the plasma membrane. Utilizing this new pH probe, we revealed neutral and acidic vesicles and substructures inside cells, highlighting compartments of distinct pH throughout the endomembrane system. These data demonstrate, that this novel pH sensor, pH-Lemon, is very suitable for the study of local pH dynamics of subcellular microstructures in living cells.

| S-EPMC6488996 | biostudies-literature

Efficiently activated ε-poly-L-lysine production by multiple antibiotic-resistance mutations and acidic pH shock optimization in Streptomyces albulus.

Project description:ε-Poly-L-lysine (ε-PL) is a food additive produced by Streptomyces and is widely used in many countries. Working with Streptomyces albulus FEEL-1, we established a method to activate ε-PL synthesis by successive introduction of multiple antibiotic-resistance mutations. Sextuple mutant R6 was finally developed by screening for resistance to six antibiotics and produced 4.41 g/L of ε-PL in a shake flask, which is 2.75-fold higher than the level produced by the parent strain. In a previous study, we constructed a double-resistance mutant, SG-31, with high ε-PL production of 3.83 g/L and 59.50 g/L in a shake flask and 5-L bioreactor, respectively. However, we found that R6 did not show obvious advantages in fed-batch fermentation when compared with SG-31. For further activation of ε-PL synthesis ability, we optimized the fermentation process by using an effective acidic pH shock strategy, by which R6 synthetized 70.3 g/L of ε-PL, 2.79-fold and 1.18-fold greater than that synthetized by FEEL-1 and SG-31, respectively. To the best of our knowledge, this is the highest reported ε-PL production to date. This ε-PL overproduction may be due to the result of R99P and Q856H mutations in ribosomal protein S12 and RNA polymerase, respectively, which may be responsible for the increased transcription of the ε-poly-lysine synthetase gene (pls) and key enzyme activities in the Lys synthesis metabolic pathway. Consequently, ε-PL synthetase activity, intracellular ATP, and Lys concentrations were improved and directly contributed to ε-PL overproduction. This study combined ribosome engineering, high-throughput screening, and targeted strategy optimization to accelerate ε-PL production and probe the fermentation characteristics of hyperyield mutants. The information presented here may be useful for other natural products produced by Streptomyces.

| S-EPMC6528598 | biostudies-literature

Mycobacterium tuberculosis transcriptional responses to acidic pH and carbon source

Project description:The purpose of this study was to examine how Mtb integrates acidic pH and available carbon sources as environmental cues to regulate its metabolism and growth rate. RNA-seq transcriptional profiling of M. tuberculosis growing at acidic or neutral pH, in pyruvate or glycerol, was examined. These studies identified carbon source-dependent and -independent pH-dependent adaptations.

2014-07-07 | GSE52020 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data