Sensitive TRP Channels
(The following is an excerpt from my paper, "Solving the Riddle of Chemical Sensitivity: The Importance of TRP Chanels," which can be downloaded form the Home page of this site.)
Once upon a time, we humans roamed the earth in small hunter-gatherer bands, looking for sustenance. In order to keep ourselves alive and find food that would nourish us, we acquired an acute sensitivity to our environment, allowing us to perceive different temperatures, tastes and smells. This is where the handy dandy Transient Receptor Potential (TRP) ion channel came in.
Technically, TRP is a protein manufactured inside human cells according to instructions from specific TRP genes in our DNA. Once assembled, the protein moves to the surface of the cell, where it sits embedded in the cell membrane, ready for stimulation. Upon activation by the particular molecules it is designed to respond to, the TRP protein changes its shape and opens a ‘channel,’ allowing mineral ions (usually calcium ions) to flow from extracellular fluid into the cell. These ions excite the cell, reversing its polarity and causing it to fire off an “action potential,” an electrical signal that moves through the nervous system to the brain, which then interprets this signal as a sensation. Meanwhile, the activation of the TRP channel has also released a flood of neurotransmitters and other chemical compounds like histamine that instruct different parts of the body how to respond to that particular molecule.
It was chemosensory TRP channels which protected our hunter-gather ancestors from the extreme-tasting chemicals in different plants and foods that could be harmful to us. As one researcher explains, plants try “to discourage predators by the unusual sensory quality of spices. [Yet] by some strange perversion, humans have learned to enjoy low doses of these deterrent chemicals,” and over time the naturally occurring chemicals in spices have greatly contributed to our “gustatory pleasure.” That’s human nature all right, to love what is bad for us.
Out of 28 different TRP subtypes distributed throughout the body, several are found primarily on our sensory neurons, the specialized nociceptive cells located in the sensing apparatus (ganglia) of the central nervous system. Specifically, TRPV1, TRPA1 and TRPM8 are the body’s temperature and “spice” sensors, activated by hot and cold as well as certain compounds in plants and foods, such as the “hot” in spicy cayenne, or the “cool” in mint or menthol. TRPA1 in particular is activated by pungent compounds like cinnamon, garlic, ginger, and also the salicylate in spices and foods.
When I first read that, I jumped off my couch with a loud, “Aha!” Surely, TRPA1 was the culprit in my salicylate sensitivity. I sat back down to dig deeper into studies on this particular ion channel and found this:
"TRPA1 channels respond to a multitude of irritants with diverse origins and chemical structures… [and] may bind to a large variety of irritant molecules to induce sensory neural excitation."
Another “Aha!” ensued. I finally understood why someone with MCS could experience the exact same reaction after eating a high salicylate spice like thyme, or while standing next to someone reeking of Downey fabric softener. Both activated TRPA1 and, to a lesser degree, TRPV1. (Both are co-expressed in sensory ganglia.)
Of course, the MCS reaction is not a “normal” response to TRP channel activation. In the normal way of things, activation is quickly followed by desensitization. Once the TRP channel ‘opens’ to the influx of calcium ions, the increased intracellular calcium quickly shuts down the sensitivity of the receptor, and calcium influx basically stops. This allows the body to quickly “adapt” to various stimulants the body is exposed to without chronic overstimulation, and explains why, when one first walks into a room with a funny smell, it can seem overwhelming at first but then quickly becomes barely noticeable. It also explains how when one first gets into a hot bath, it feels very hot at first, but the body quickly adjusts. (TRPV1 is literally the heat-sensing system of the body, and in laboratory tests, TRPV1 “knockout” mice have problems sensing heat stimuli.)
The process of TRP desensitization explained to me why going on a low salicylate diet could possibly advance or exacerbate MCS. With strict avoidance, perhaps one no longer regularly desensitized TRP channels, so that they became more or less ‘virginal’ again, sensitive to the slightest stimulation. It also possibly explained why saunas were often experienced as helpful in reducing MCS symptoms. Perhaps it wasn’t the sweaty detoxification aspect after all, perhaps the heat served to desensitize thermal-sensing TRP channels.
But this begged the question, if TRP channels are normally supposed to desensitize themselves, then what exactly is happening in MCS?
Studies have shown that TRP channels can not only be desensitized, they can also become unusually hypersensitized, a process by which the cell causes TRP channels to increase in number and/or become more easily activated. Since TRP genes are responsible for how many TRP proteins the cell makes, there are genetic reasons one can overexpress the proteins (for which I could see a lot of evidence in my own family). Or, one could engage in a lifestyle which turns TRP genes on or otherwise encourages overexpression, such as a spice-heavy diet (I was a cayenne pepper freak, put it on everything). Or, a high-fruit and -vegetable diet rich in TRP-stimulating salicylates (like my two years of vegan and Paleo eating). Or, the frequent drinking of alcohol (um yes, that was me, too; I drank wine with dinner probably 4 or 5 nights a week). Indeed, the ethanol in alcoholic drinks is known to be such a potent TRP sensitizer that ethanol is sometimes used specifically for that purpose in laboratory studies.
Once overexpressed and/or hypersensitized, TRP channels release all kinds of pro-inflammatory chemicals into the body, including substance P and calcium gene-related peptide (CGRP), a well-known trigger of headaches, the most common MCS symptom. These chemicals also cause mast cell degranulation throughout our tissues, which releases a flood of histamine into the body and triggers most of the other heart-pounding MCS symptoms. This excess of chemicals not only creates the reactions so well known to MCS sufferers, it also creates what is known as an “inflammatory soup” in the body, causing neurogenic inflammation, which in turn releases still more chemicals into the body that ratchets up the sensitivity of TRP even more. It is a vicious loop inflammatory cycle that once turned on, is very difficult to turn off.
Next: Solving the Riddle