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Receptors play a role in regard to environmental toxins and in MCS

Information about some members (mainly TRPV1, TRPV3 and TRPA1) of the large group of receptors of the TRP ion channel family

I want to introduce you to some of the receptors of the TRP (transient receptor potential) ion channel family. Please keep in mind that I am not a scientist and that English is not my mother tongue.

There will be two parts. In the first part today you will find general information about several receptors of the TRP family and the role these receptors play in regard to environmental irritants and MCS. In the second part you will find a list of substances which are able to activate these receptors.

Information about different receptors of the TRP family

TRPV1

The most information can be found about the TRPV (vanilloid) subgroup and TRPA1.

The TRPV1 receptor is broadly expressed in all “port of entry” tissues (e.g., skin, gut, airways, conjunctiva) and the various cell types linings such tissues (i.e., keratinocytes, epithelia, endothelia, etc.). In addition TRPV1 receptors were found in various peripheral nonneuronal tissues (e.g., kidney, lung, testis, pancreas, spleen, liver, stomach, vascular smooth muscle, placenta, cornea, uterus, bladder). It exists in many areas of the CNS like hypothalamus, hippocampus, frontal cortex, motor neurons of the spinal cord and in CNS cells involved in inflammation (e.g. astrocytes, microglia). (Veronesi et al. (2006)

TRPV1 is gated not only by vanilloids such as capsaicin, but also by noxious heat, acidosis and intracellular lipid mediators such as anandamide, lipoxygenase products and various pro-algesic pathways.

If you read “vanilloid” it is likely that you are thinking of a piece of cake or vanilla ice cream. In addition to such a sweet food, vanillin can be found when paper becomes old (the smell of old books). But in contrast to your expectation vanilloids are substances, which are often hot and pungent like capsaicin in chillies. I am sure you know that burning sensation in your mouth if you have eaten something hot and spicy. This feeling of pain is caused by SP (substance P), which the TRPV1 releases together with neurokinin A [NKA], and calcitonin-gene-related-peptide [CGRP], which are leading to an inflammatory response.

In addition various cell types, including mast cells, epithelial cells, and immune cells, have been shown to release pro-inflammatory cytokines (e.g., IL1beta, IL6, IL8, and TNF) in response to SP, CGRP, and NKA. (Veronesi 2006)

After a while SP is used up and the result is that you will feel a reduction of pain (desensitization). Because of this mechanism capsaicin is sometimes used as a treatment in medicine.

The problem with this is, that damage or even the death of cells, mentioned in several articles, can take place:

“Cell death was characterized by cytoplasmic swelling, coalescence contents and eventual lysis” (Berkley Molecular Neurobiology Student Manuscripts- Term Paper Code 53)

“After using capsaicin, the inflammatory reaction and lipid peroxidation may affect cellular functions and lead to cell death.” (Richeux et al. 2000)

“Activation of the capsaicin receptor (VR1 or TRPV1) in bronchial epithelial cells by capsaicinoids and other vanilloids promotes pro-inflammatory cytokine production and cell death.” (Reilly 2005)

“We show that activation of the intracellular subpopulation of TRPV1 causes endoplasmic reticulum (ER) stress and cell death in human bronchial epithelial and alveolar cells.” (Thomas et al. 2007)

“In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeability-increasing effect via substance P. It also plays a role in the immediate blood-brain barrierr disruption following ischaemia-reperfusion.” (Hu et al. 20005)

“Activation of TRPV1 excites sensory neurons and induces the accumulation of intracellular Ca2+. This results in excessive mitochondrial Ca2+ loading and subsequent mitochondrial disruption, leading to neuronal cell death.”(Kim 2006)

“We recently reported that cytochrome c release from damaged mitochondria and caspase-3 activation are required for TRPV1-mediated neurodegeneration in mesencephalic cultures.” (Kim 2006)

TRPV3

The TRPV3 receptor is another member of the TRPV family. It behaves in a similar way as TRPV1. It can be activated by substances like camphor, carvacrol and thymol.

In the article by Vogt-Eisele et al. 2007 terpenoids in essential oils, which are used cosmetically, were studied as agonists for TRPV3.

TRPA1

TRPA1 can be activated by allyl isothiocyanate, which you can find in mustard oil (cabbage, cress…) or by the thiosulfinate allicin (garlic and onions).

TRPA1, also plays an important role in modulating nociceptor excitability and neurogenic inflammation in the setting of tissue injury. Bradykinin is produced in response to tissue injury, inflammation and ischemia and it binds to the PLC-coupled receptors on sensory neurons. It causes acute pain through immediate excitation of nociceptors like TRPA1, followed by a longer sensitization of thermal and mechanical stimuli. This hypersensitization is produced through PLC-mediated potentiation of TRPV1. TRPA1 is often coexpressed with TRPV1. (Bautista et al. 2006)

TRPM2

Peroxynitrite and other reactive species induce oxidative DNA damage and activate poly(ADP-ribose) polymerase 1 (PARP-1).

Overactivation of PARP-1 depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways (Pacher, Szabo 2008)

TRPM2 is gated by (PARP-1). (Pacher, Szabo 2008)

TRPM8

This receptor is responsible for sensing cool temperatures. If you eat menthol, it gives you a cool feeling, which is created by the activation of this receptor.

These receptors play a role in regard to environmental toxins and in MCS

I want to share now a few quotes in regard to sensitization of the receptors with you.

“In general, sensitization may be governed by a change in conformation status of the receptor or ion channel itself, rendering an enhanced activation state. Sensitization may further be governed by increased expression of functional receptors on the cell surface.” (Veronesi and Oortgiesen 2006)

“In particular, upregulation of TRPV1 is often produced after exposure to proinflammatory agents, thus suggesting the general hypothesis that under inflammatory circumstances, a ‘sensitized’ TRPV1 can be activated by agonist concentrations much lower than those tested under conventional experimental conditions.” (Geppetti 2004)

“Furthermore, activation by one ligand can potentiate the response to a second activator.” (Kauer 2008)

In several articles researchers of different teams looked at environmental irritants and their role in activation/sensitization of these receptors:

Toxicologists have reported an initiating role for TRPV1 in mediating airway inflammation (e.g., hyperresponsiveness, asthma) caused by chemical irritants and air pollutants (e.g., particulate matter, ozone, pesticides (Veronesi et al., 2001 )). Identifying this receptor as a common responder to multiple chemical toxicants could explain how diverse pollutants and inhaled substances produce the respiratory dysfunction associated with environmental contaminants. (Veronesi and Oortgiesen 2006)

In the article by Andre et al. (2008) is mentioned that unsaturated aldehydes (mainly acrolein and crotonaldehyde) in cigarette smoke stimulated TRPA1 and caused airway neurogenic inflammation.

Acrolein is present in tear gas, vehicle exhaust, and smoke from burning vegetation, including tobacco products. Acrolein can induce apnea, shortness of breath, cough, airway obstruction, and mucous secretion. It is also a toxic metabolite of cyclophosphamide and ifosfamide, chemotherapeutic agents widely used in the treatment of cancer, severe arthritis, multiple sclerosis, and lupus. (Bautista et al. 2006)

Shiba et al. (2009) found out that phthalate esters are able to activate TRPV1 and TRPA1 receptors.

Macpherson showed in 2007 that formaldehyde activates the ion channel TRPA1. In addition it was discovered that the endogenous aldehyde hydroxynonenal is able to activate TRPA1, too.

It is produced when reactive oxygen species peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress and it promotes acute pain, neuropeptide release, and neurogenic inflammation. (Trevisani 2007)

Cyclohexanone is known to activate TRPV1 and it is used as an intermediate in the production of nylon, fungicices, herbicides, paint thinners and lubricant oils. (Silver et al. 2006)

But the most important work was done by Pall and Anderson (2004). They investigated the role of many substances especially solvents and VOCs in regard to the TRP ion channels and they mention in their article 12 points, which provide the support that TRPVs plays a role in MCS. Here are a few examples:

  • Chemicals, which stimulate the TRP receptors are similar to the diversity to chemicals in MCS.
  • TRPVs increase NO and stimulate NMDA receptors.
  • Substance P is increased on vanilloid stimulation and it is elevated in MCS
  • Neurogenic inflammation is caused by the activation of TRPVs and it plays a role in MCS

Professor Pall describes the connection between the receptors of the TRP family, NO and the NMDA receptor as follows:

“The vanilloid receptor (TRPV1 or VR1), widely distributed in the central and peripheral nervous system, is activated by a broad range of chemicals similar to those implicated in Multiple Chemical Sensitivity (MCS) Syndrome. The vanilloid receptor is reportedly hyperresponsive in MCS and can increase nitric oxide levels and stimulate N-methyl-D-aspartate (NMDA) receptor activity, both of which are important features in the previously proposed central role of nitric oxide and NMDA receptors in MCS. Vanilloid receptor activity is markedly altered by multiple mechanisms, possibly providing an explanation for the increased activity in MCS”(Pall and Anderson 2004)

While I worked on this subject I had the feeling I looked through a keyhole. I was able to see some parts of the room in front of me, but other parts I was not able to see. I am convinced that during the next years more parts of the “room” will be discovered and we will get a bigger view in which in additional areas, these receptors play a role and maybe even more substances will be discovered by which these receptors are activated.

Author: Namid

References:

First I want to give you a few additional links to articles, which I found helpful:

Geppetti, P., et al. (2006). The transient receptor potential vanilloid 1: role in airway inflammation and disease. Eur J Pharmacol. 2006 Mar 8;533(1-3):207-14.

Geppetti et al (2004).: Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function. British Journal of Pharmacology (2004) 141, 1313-1320

If you want to read more about the role of these receptors in diseases I would recommend that you read Nilius et al.:Transient Receptor Potential Cation Channels in Disease. Physiol. Rev. 87: 165-217, 2007

It contains several good figures like: fig. 7 – TRPV1, fig.8 – TRPA1, fig. 11- respiratory tract.

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This entry was posted on Monday, August 10th, 2009 and is filed under Chemical Exposure, Chemical Sensitivity, MCS, Clinical Diagnostics, Database, Diagnosis Chemical Injury, Environmental Exposure, Environmental Illnesses, Neurotoxicity, Toxicology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response or Trackback from your own site.

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