TRPA1, Hypoxia and ME?

David S. Bell has written the book: “Cellular Hypoxia and Neuro-Immune Fatigue”. http://www.davidsbell.com/DSBBooks.htm

So, hypoxia and neuro-immune fatigue have already been linked together. I will not go further into that subject, but I will give you a few good quotes and links to the connection between TRPA1 and hypoxia:

“Monitoring oxygen (O2) levels is essential to optimizing aerobic metabolism and ensuring proper biological processes in most eukaryotes. The spice chemosensor TRPA1 is a previously unidentified O2 sensor in the mammalian sensory nervous system that warns against hyperoxia and hypoxia.”
Reference: Channels: A TR(i)P in the air
http://www.nature.com/nchembio/journal/v7/n10/full/nchembio.669.html

“Oxygen (O(2)) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O(2), it is critical to elucidate the molecular mechanisms responsible for O(2) sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O(2). O(2) sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O(2)-dependent inhibition on TRPA1 activity in normoxia, direct O(2) action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O(2)-sensing mechanism mediated by TRPA1.”
Reference: TRPA1 underlies a sensing mechanism for O2
http://www.ncbi.nlm.nih.gov/pubmed/21873995

“…Recent studies have revealed that changes in the availability of molecular oxygen (O2) also control the activation of TRP channels. Anoxia induced by O2-glucose deprivation and severe hypoxia (1% O2) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O2) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H2S) and carbon dioxide (CO2). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels.”
Reference: TRP channels: sensors and transducers of gasotransmitter signals
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429092/

“In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-α and interleukin-1α) induced TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). HIF1α unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn(2+), suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1α mechanism that links inflammatory mediators to ion channel expression.”
Reference: Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.
http://www.ncbi.nlm.nih.gov/pubmed/22843691

“We concluded that acute intermittent hypoxia (AIH) sensitizes lung vagal C fibers (LVCFs) in rats, thus resulting in exaggerated airway reflexogenic responses to chemical stimulants, possibly by ROS action and activation of TRPA1 receptors.”
Reference: Hypersensitivity of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1
http://www.ncbi.nlm.nih.gov/pubmed/23076873

Mitochondrial dysfunction - influence on TRPA1

In my last blogposts I have brought links to many articles informing that the ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) is affected in a number of diseases/conditions, which has relation to Myalgisk encephalomyeltitis (ME). This is Multiple Chemical Sensitivity (MCS), inflammation, pain (fibromyalgia), autonomic dysfunction, Irritable Bowel Syndrome (IBS), bladder pain syndrome and neuropathy.

TRPA1 and the ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) are also involved in a condition called exercise-induced anaphylaxis. And something is wrong about exercise and ME. Is there a shared biochemistry?

Thus, it is reasonable to suspect TRPA1 is affected in ME.

For many years researchers have looked at the relationship between ME and mitochondrial dysfunction. It is an obvious idea to see how TRPA1 and TRPV1are affected by mitochondrial dysfunction.

There is growing evidence that the mitochondrial dysfunction contributes to the complex mechanism of many diseases. Increased formation of Reactive Oxygen Species (ROS) are suspected to contribute to the chronic inflammatory condition in many diseases such as Type II diabetes, cardiovascular disease, and neuroinflammation. And we already know ROS are elevated in ME.

Mitochondrias and TRPA1 are found in peripheral terminals of sensory nerves. A group of researchers wanted to investigate how ROS from mitochondrial dysfunction could affect TRPA1 (and TRPV1). For this experiment they used "bronchopulmonary C fibers" (the nerve fiber, which is connected to the lungs) from mice.

The experimental description can be read by the article mentioned below. I am just quoting the exciting conclusion:
" In conclusion, we present evidence that acute mitochondrial dysfunction activates airway sensory nerves preferentially via TRPA1 through the actions of mitochondrially-derived ROS. This represents a novel mechanism by which inflammation may be transduced into nociceptive electrical signaling."

Now, we know that TRPA1 and mitochondrial dysfunction are linked together. Can we use this knowledge in the research into ME and co-morbid conditions?

Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves Via Transient Receptor Potential (TRP) Channels
http://www.ncbi.nlm.nih.gov/pubmed/23444014

More knowledge about TRPA1:
Chapter 11 TRPA1 : A Sensory Channel of Many Talents
http://www.ncbi.nlm.nih.gov/books/NBK5237/

In Danish - på dansk:

Mitokondrie dysfunktions påvirkning af TRPA1
I de seneste blogindlæg har jeg bragt links til en lang række artikler, der viser at ion kanalen Transient Receptor Potential Ankyrin 1 (TRPA1) er påvirket i en lang række sygdomme/tilstande, som har relation til Myalgic encephalomyeltitis (ME). Det drejer sig om Multiple Chemical Sensitivity (MCS), inflammation, smerte (fibromyalgi), autonom dysfunktion, Irritable Bowel Syndrome (IBS), kronisk smertefuldt blæresyndrom og neuropati.

TRPA1 er også sammen med ion kanalen Transient Receptor Potential Vanilloid 1 (TRPV1) involveret i en tilstand kaldet motionsinduceret anafylaksi. Og der noget galt med motion og ME. Så mon ikke der kunne være noget overlappende biokemi for disse tilstande?

Der er således begrundet mistanke til at kigge nærmere på, om der kan opstilles en hypotese om TRPA1 er påvirket i ME.

Igennem mange år har forskere set på sammenhæng mellem ME og mitokondrie dysfunktion. Det er derfor en nærliggende tanke at om TRPA1 og TRPV1 påvirkes af mitokondrie dysfunktion.

Der er en voksende bevismængde, der viser at mitokondrie dysfunktion bidrager til den komplekse mekanisme i mange sygdomme. Øget dannelse af Reactive Oxygen Species (ROS) er mistænkt for at bidrage til den kroniske inflammatoriske tilstand i mange sygdomme som f. eks. type II diabetes, kardiovaskulær sygdom og neuroinflammation. Og vi ved allerede, at ROS er forhøjet hos ME patienter.

Mitokondrier og TRPA1 findes i perifere terminaler af sensoriske nerver. En gruppe forskere ønskede at undersøge, hvordan ROS fra mitokondrie dysfunktion kunne påvirke TRPA1 (og TRPV1). Til forsøget anvendte de ”bronchopulmonary C-fibres” (nervefiber, der har forbindelse til lungerne) fra mus.

Selve forsøgsbeskrivelsen kan læses af nedennævnte artikel. Jeg vil blot opridse den spændende konklusion:

”Det kan konkluderes, at vi fremviser evidens for, at akut mitokondrie dysfunktion aktiverer luftvejenes sensoriske nerver fortrinsvis via TRPA1 igennem virkningen af mitokondrie- afledt ROS. Dette repræsenterer en ny mekanisme ved hvilken inflammation kan omformes til nociceptiv elektrisk signalering.”

Nu ved vi altså, at TRPA1 og mitokondrie dysfunktion hænger sammen. Kan vi udnytte denne viden i forskning i ME og ko-morbide tilstande? 

Reference:
Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves Via Transient Receptor Potential (TRP) Channels
http://www.ncbi.nlm.nih.gov/pubmed/23444014

Og mere viden om TRPA1:
Chapter 11 TRPA1 : A Sensory Channel of Many Talents
http://www.ncbi.nlm.nih.gov/books/NBK5237/

Artikel om mitokondrie sygdomme på dansk
http://www.ugeskriftet.dk/LF/UFL/2003/07/pdf/VP38126.pdf

Exercise and...TRPA1 and TRPV1

I do find some weird information when looking for information on exercise...

"Exercise-induced anaphylaxis (EIA) is a rare disorder in which anaphylaxis occurs after physical activity. The symptoms may include pruritus, hives, flushing, wheezing, and GI involvement, including nausea, abdominal cramping, and diarrhea. If physical activity continues, patients may progress to more severe symptoms, including angioedema, laryngeal edema, hypotension, and, ultimately, cardiovascular collapse." Reference

A disease where you get sick of exercise...that reminds me of something....

But what mechanisms are involved in this disease? You will not believe it - once again TRPA1:

"This review mainly focuses on TRPV1 and TRPA1 and the role they have in the allergic response and how these receptors may be influenced in exercise-induced anaphylaxis.":
Transient receptor potentials (TRPs) and anaphylaxis

From the article:
Exercise-induced anapylaxis is likely to involve both TRPV1 and TRPA1 ion channels. Exercise is an oxidative state, with the individual consuming more oxygen and generating  a range of compounds including superoxide anions, hydoxyl radicals, and hydrogen perioxide. TRPA1 is the main oxidant receptor and the ion channel activates on sensing these irritant compounds. Importantly, it acts as a direct sensor of oxygen and is activated during hypoxia. Serotonin and bradykinin also increase with exercise influencing priming of TRPV1.

ME, neuropathy, TRPA1

Some ME patients tell me that they have developed neuropathy. And in these day I am trying to find out everything about ME, TRPA1 and ME co-morbidities.

So I searched the internet for the connection between ME/CFS, TRPA1 and neuropathy. This is some of the informations I found:

Research presented at the 2010 annual meeting of the American Academy of Neurology meeting (poster P05.231) showed a connection between fibromyalgia, chronic fatigue syndrome and neuropathy.  Reference

Andersson Kings College London informs that they have identified reactive oxygen species and methylglyoxal as key mediators responsible for the development of diabetic neuropathy. These mediators act by stimulating the ion channel TRPA1 in pain-sensing neurons, thereby producing pain and neuropathy. Methylglyoxal is a glucose metabolite that occurs at higher concentrations during hyperglycemia in diabetes.

Further reading here:

Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy

Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies

And from this article  I found: “TRPA1 is also involved in persistent to chronic painful states such as inflammation, neuropathic pain, diabetes, fibromyalgia, bronchitis and emphysema.”

The researchers from this study present evidence for functional expression of excitatory TRPV1, TRPA1, and inhibitory CB1 receptors along the sensory fibers of the vagus nerve which lend pathophysiological relevance to the axonal membrane and the control of neuropeptide release that may become important in cases of inflammation or neuropathy. Sensitization and possible ectopic discharge may contribute to the development of autonomic dysregulation in visceral tissues that are innervated by the vagus nerve.

MAYO CLINIC mentions that you can discuss the use of alpha-lipoic acid with your doctor as a treatment for peripheral neuropathy.

TRPA1 involvement in autonomic dysfunction in ME?

In my previous blog posts I referred to articles that make it plausible that TRPA1 is involved in the biochemistry of co-morbid ME conditions like Multiple Chemical Sensitivity and inflammation/pain.

But what about autonomic dysfunctions like Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance? Is there a connection? Is TRPA1 involved in regulation of the vasculature?

The answer is: YES, TRPA1 and other TRP channels have influence on regulation of the vasculature.

My favorite article today is this one:
Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo

The conclusion from this article:
“TRPA1 is involved in mediating vasodilation. TRPA1 can also influence changes in blood pressure of possible relevance to autonomic system reflexes and potentially to vasovagal/neurocardiogenic syncope disorders.”

There are other fine articles describing TRP in the vasculature:

TRPA1 channels in the vasculature

Transient receptor potential channels and vascular function


Cerebral Blood Flow and TRP

We already know that Cerebral Blood Flow is disturbed in ME/CFS patients:

Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome


…and these articles describe the connection between TRP and Cerebral Blood Flow:

Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow

Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels


The connection between chemical sensitivity, TRPA1 and cerebral blood flow

TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation

TRPA1/TRPV4/PAR in inflammation/pain

Injury and inflammation trigger the activation of proteases from the circulation, immune cells and epithelial tissues that regulate cells by cleaving protease-activated receptors (PARs), members of a family of four G protein coupled receptors (GPCRs).

These G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain.

PAR2 is co-expressed with substance P and calcitonin gene-related peptide by a subpopulation of primary spinal afferent neurons that control neurogenic inflammation and pain transmission. Activation of PAR2 on sensory nerve endings evokes the local release of these neuropeptides, which stimulate extravasation of plasma proteins, infiltration of neutrophils and vasodilation (neurogenic inflammation). PAR2 activation also promotes the central release of neuropeptides that activate second order spinal neurons that transmit pain. These mechanisms contribute to painful inflammation of the intestine, pancreas and joints. Therefore, it is of considerable interest to understand the mechanisms by which PARs regulate the activity of nociceptive neurons.

Members of the TRP family, including TRPV1, TRPV4 and TRPA1 mediate neurogenic inflammation and pain, and are major down-stream targets of PAR2 . Activation of these non-selective cation channels stimulates the influx of extracellular Ca2+ ions and the release of neuropeptides in peripheral tissues and the spinal cord, which induces neurogenic inflammation and pain. During injury and inflammation, several factors are generated that can directly activate these channels. Elevated temperatures, protons and lipid mediators activate TRPV1, mechanical shear stress, osmotic stimuli and lipid mediators activate TRPV4, and products of reactive oxygen species and reactive prostaglandin metabolites activate TRPA1. However, indirect mechanisms, particularly those triggered by GPCRs, play a prominent role in TRP channel activation. Many GPCRs that induce neurogenic inflammation and pain indirectly regulate TRP channels, which mediate their pro-inflammatory and pronociceptive actions.

Reference: Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) Coupling is Required for Sustained Inflammatory Signaling


I think it is of particular interest, that TRP can be activated of Reactive Oxygen Species (ROS), because oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms


Some researchers believe that ME/CFS, fibromyalgia, irritable bowel syndrome and other pain syndromes share a common biochemistry via sensitization. This review article describes TRPA1 mediated neural cross-talk induced by oxidative stress as model for some pain syndromes:

TRPV1 and TRPA1 act as a nocisensor to mediate not only an afferent signal to the dorsal horn of the spinal cord, but also an efferent signal in the periphery through secretion of inflammatory agents, such as substance P and calcitonin gene-related peptide in nociceptive sensory neurons.

Peripheral inflammation produces multiple inflammatory mediators that act on their cognate receptors to activate intracellular signal transduction pathways and thereby modify the expression and function of TRPV1 and TRPA1 (peripheral sensitization). During tissue damage and inflammation, oxidative stress, such as reactive oxygen species or reactive carbonyl species is also generated endogenously.

The highly diffusible nature might account for the actions of free radical formation far from the site of injury, thereby producing systemic pain conditions without central sensitization through neural cross-talk.

Reference: Transient receptor potential A1 receptor-mediated neural cross-talk and afferent sensitization induced by oxidative stress: implication for the pathogenesis of interstitial cystitis/bladder pain syndrome

A thorough description of ROS and TRP is provided in this article:
Role of Reactive Oxygen Species and Redox in Regulating the Function of Transient Receptor Potential Channels

And further description of peripheral sensitization influenced by chemokines/TRP activation is found in this article: Chemokines as Pain Mediators and Modulators 

This knowledge opens the possibility that TRPA1 antagonist can be used against inflammatory pain:
Patent application: NOVEL TRPA1 ANTAGONISTS

Transient Receptor Potential in Multiple Chemical Sensitivity

I have previously written about Transient Receptor Potential Ion Channels, because they are mentioned in research on ME/CFS and co-morbid conditions.

TRP is also involved in chemosensation and maybe in Multiple Chemical Sensitivity (MSC).

TRPA1/TRPV1 in chemosensation

Transient Receptor Potential Ankyrin 1 (TRPA1) is a member of the TRP family. TRPA1 function as a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species and noxious constituents of smoke and smog, initiating irritation and airway reflex responses.

Together with Transient Receptor Potential Vanilloid 1 (TRPV1), TRPA1 may contribute to chemical hypersensitivity, chronic cough and airway inflammation in asthma.

Trigeminal chemosensory nerve endings in the nasal mucosa are in the first line of defense against noxious chemical challenges.

TRPA1 is expressed in 20–36.7 percent of trigeminal neurons, 20–56.5 percent of dorsal root ganglion neurons, and 28.4 percent of neurons in nodose ganglia.

Neuropeptides such as Substance P and Calcitonin Gene Related Peptide (CGRP), released from chemically stimulated nerve endings, promote neurogenic inflammatory vasodilation and leakage, contributing to narrowing or obstruction of the nasal passages.

Since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond much more strongly. With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity. This cumulative effect may result in robust TRPA1-induced irritation even at low sub-acute exposure levels, for example during periods of increased photochemical smog exposures, or low level indoor air pollution. Once irreversibly modified, channels may remain active for extended periods of time even when the irritant stimulus is removed.

(I think it is interesting that TRPA1 reacts more strongly when glutathione is depleted, because a study found decreased levels of cortical glutathione in CFS patients )

Reference: Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control

Reference: Chapter 11 TRPA1 : A Sensory Channel of Many Talents


Research on this topic is to be found in the Project Reporter from National Insitutes of Health

Project Leader Gerry Oxford has this project:
ROLE OF TRP CHANNELS IN ENVIRONMENTAL IRRITANT-INDUCED HEADACHE DESCRIPTION

“Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple Chemical Sensitivity (MCS).”

“It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium.In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms.”

The knowledge about TRPA1 is used in a patent application:
Treatment of Respiratory Disorders using TRPA1 Antagonists