Are CELF4, SCN8A, TRPV1 and TRPA1 involved in Multiple Chemical Sensitivity?

A CELF4 DNA variation rs1166424 showed up in patients with fibromyalgia in a preprint of this study (1):
The genetic architecture of fibromyalgia across 2.5 million individuals

A CELF4 DNA variation rs948440 showed up in patients with Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) in this study (2):
Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

Some patients with fibromyalgia and some patients with ME/CFS have Multiple Chemical Sensitivity (MCS). Could deficiency of the gene CELF4 be involved?

The CELF4, SCN8A, TRPV1 and TRPA1 interaction

In neurons CELF4 deficiency results in a dramatic elevation in the expression of Nav1.6 protein encode by the gene SCN8A. SCN8A interacts with TRPV1 and TRPA1. 

Using STRING Protein-Protein Interaction Networks it look like this, https://string-db.org/ :

Details about CELF4, SCN8A, TRPV1 and TRPA1

This study informs us about CELF4 (3):

The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity

Quote from reference 3:
"CELF4 is a powerful negative regulator of sensory neuron excitability and sensory thresholds to heat and mechanical stimuli resulting in thermal and mechanical hypersensitivity in uninjured mice and exacerbating hypersensitivity in injured mice."

"CELF4 expression is most highly enriched in small to medium diameter neurons that co-express the capsaicin receptor, TRPV1"

"Capsaicin-sensitive Celf4 KO neurons are robustly hyperexcitable"
(KO=Knock-Out)


This study also informs us about CELF4 (4):
Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice
Quote from reference 4:"
"In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Nav1.6 protein at the AIS in both null and heterozygous neurons."
(AIS = axon initial segment. SCN8A encodes the protein Nav1.6.)

This study informs us about TRPV1 and TRPA1 (5):
The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization.
Quote from reference 5:
"TRPV1’s interaction with TRPA1 channels further influences chronic pain onset and progression."

This study informs us about TRPV1 and TRPA1 in MCS (6):

Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity

Quote from reference 6:

"There are interacting and overlapping pathophysiological features of responses to environmental exposures that are associated with neurodegeneration and MCS. These include genotypes for detoxification, oxidative stress, systemic inflammation, disruption of the BBB, chronic pain, central sensitization, decreased cognition and upregulation of TRPV1 and TRPA1 receptors."

Answers from Artificial Intelligence about MCS and CELF4, SCN8A, TRPV1, TRPA1

I used Artificial Intelligence (AI) via https://www.google.com/

Me: Is CELF4 is involved in hypersensitivity responses that are relevant to multiple chemical sensitivity?

AI: Yes, the CELF4 protein is involved in hypersensitivity responses, specifically through its role in regulating sensory neuron excitability. It acts as a negative regulator of both mechanical and heat sensitivity in sensory neurons, meaning its absence or reduction can lead to hypersensitivity similar to that seen in conditions like multiple chemical sensitivity. Research shows that when CELF4 is reduced, mice exhibit enhanced mechanical and heat hypersensitivity. 

• CELF4 is a negative regulator: The protein CELF4 functions as a brake on sensory neuron excitability.
• Loss of CELF4 increases sensitivity: When CELF4 is not functioning properly, sensory neurons become more "excitable," leading to heightened sensitivity to mechanical and heat stimuli.
• Evidence from studies: Experiments have demonstrated that mice lacking sufficient CELF4 display a greater response to stimuli like heat and pressure, showing clear mechanical and thermal hypersensitivity.
• Relevance to multiple chemical sensitivity: The hypersensitivity observed in these studies is relevant to conditions like multiple chemical sensitivity, which is characterized by an overreaction of the nervous system to various chemical triggers. 

Me: Is Nav1.6 involved in Multiple Chemical Sensitivity?

AI: While there is no direct evidence that Nav1.6 is involved in Multiple Chemical Sensitivity (MCS), there is research suggesting that Nav1.6 channels can be affected by certain toxins, and that these toxins can impact neuronal excitability, which is a potential mechanism for MCS-like symptoms. For example, exposure to deltamethrin (DM), a pyrethroid insecticide, can alter the function of Nav1.6 channels and lead to changes in neuronal excitability in certain cell types. Also, Nav1.6 in sensory neurons is known to be involved in pain signaling and can be modulated by toxins, which could potentially contribute to the sensory and pain-related aspects reported by individuals with MCS. 

Nav1.6 and toxin exposure

• Deltamethrin (DM) exposure: Studies have shown that DM can affect Nav1.6 channels in certain neurons, specifically in the nucleus accumbens (MSNs). This can lead to changes in both the persistent and tail current densities of these channels.
• Impact on neuronal excitability: By altering Nav1.6 function, DM may affect the overall excitability of these neurons. This could provide insights into the initial mechanisms of injury from toxin exposure, which could be relevant to MCS symptoms. 

Nav1.6 and sensory neurons

• Pain and touch: Nav1.6 is a key sodium channel in sensory neurons that are responsible for transmitting pain and touch signals.
• Pain signaling: Increased Nav1.6 activity can enhance responses to pain, while reducing Nav1.6 can alleviate pain in animal models of inflammation and nerve injury. This suggests that Nav1.6 plays a significant role in pain perception, which is a common symptom in MCS. 

Conclusion

While more research is needed to establish a direct link between Nav1.6 and MCS, the available evidence suggests that Nav1.6 could be a potential factor. The channel's role in transmitting sensory signals and its sensitivity to certain toxins means it could contribute to the development or exacerbation of MCS symptoms like pain and altered sensory perception. 

Me: How does CELF4, Nav1.6 and TRPV1 interact?

AI: CELF4 negatively regulates the synthesis of Nav1.6, while TRPV1 can modulate Nav1.6 currents. CELF4 is a negative regulator of sensory neuron excitability, and when its function is impaired, it can lead to sensory hypersensitivity. TRPV1 activation increases Nav1.6 currents, which is an important interaction because TRPV1 is involved in pain perception. Therefore, the interaction between these three proteins is complex: CELF4 limits the availability of Nav1.6, and TRPV1 can directly increase the activity of available Nav1.6, together regulating neuronal excitability and sensory input. 

Interactions

• CELF4 and Nav1.6: CELF4 negatively regulates the synthesis of the Nav1.6 sodium channel, meaning less CELF4 activity leads to more Nav1.6 protein available to the neuron.
• TRPV1 and Nav1.6: Activation of TRPV1 by agonists like capsaicin increases the amplitude of Nav1.6 currents. This suggests a direct functional interaction where TRPV1 activity can enhance the excitability of neurons that have Nav1.6 channels.
• CELF4 and TRPV1: CELF4 is enriched in sensory neurons and acts as a negative regulator of sensory neuron excitability. It also targets mRNAs involved in synaptic development, which would indirectly affect the function of other proteins like TRPV1, influencing sensory thresholds. 

How the interactions regulate neuronal excitability

• When CELF4 is present and functional, it limits the amount of Nav1.6, which dampens overall neuronal excitability.
• When CELF4 is deficient, more Nav1.6 is synthesized, leading to increased neuronal excitability and sensory hypersensitivity.
• Activation of TRPV1 in a neuron with available Nav1.6 channels can further increase the neuron's excitability by boosting the sodium current.
• These interactions are crucial for the nervous system to finely tune sensory information and neuronal activity. 

Me: Is TRPV1 involved in Multiple Chemical Sensitivity?

Yes, the TRPV1 receptor is implicated in Multiple Chemical Sensitivity (MCS), as research shows it can become sensitized and hyperresponsive in individuals with MCS. This sensitization leads to a heightened sensitivity to a wide range of chemicals and is supported by evidence such as capsaicin inhalation studies and brain imaging that show altered neuronal activity in response to TRPV1 activation in MCS patients. 

• Sensitization: The TRPV1 receptor, along with the TRPA1 receptor, appears to be sensitized in people with MCS. This means the receptors are more easily triggered than in non-sensitive individuals.
• Chemical activation: TRPV1 is activated by various substances involved in MCS, including capsaicin. Studies have shown that individuals with MCS exhibit a hyperresponsive TRPV1 receptor, which is consistent with the heightened chemical sensitivity they experience.
• Nitric oxide and NMDA receptors: Hyperresponsiveness of TRPV1 in MCS may contribute to increased nitric oxide (NO) levels and N-methyl-D-aspartate (NMDA) receptor activity, which are factors thought to play a central role in the condition.
• Brain imaging: Functional brain imaging studies have provided further support for the role of TRPV1 by showing that its activation in MCS patients leads to brain-region-specific neuronal variations not seen in controls.

Me: Is TRPA1 involved in Multiple Chemical Sensitivity?

AI: Yes, the TRPA1 receptor is involved in Multiple Chemical Sensitivity (MCS), as it is one of the key transient receptor potential (TRP) channels that appear to be sensitized in individuals with MCS. This sensitization can lead to an exaggerated response to environmental irritants and chemicals, contributing to the hypersensitivity symptoms experienced by those with the condition. 

• Sensitization of TRP receptors: TRPA1, along with TRPV1, is part of a group of sensory receptors that appear to be overactive in people with MCS.
• Exaggerated responses: This sensitization means that TRPA1 receptors can trigger a stronger inflammatory and irritative response to chemicals that would normally not cause such a strong reaction.
• Contribution to symptoms: The activation of TRPA1 by irritants can lead to symptoms like respiratory irritation and headaches, which are common in MCS, notes ScienceDirect and the National Institutes of Health.
• Role in inflammation: The activation of TRPA1 can trigger a cascade of events, including the release of inflammatory neuropeptides, which contributes to symptoms like neurogenic inflammation.
• Growing scientific consensus: Research is increasingly supporting the biological basis for MCS, moving away from the view that it is purely psychological. 

References:

1) The genetic architecture of fibromyalgia across 2.5 million individuals
Isabel Kerrebijn, Gyda Bjornsdottir, Keon Arbabi, Lea Urpa, Hele Haapaniemi, Gudmar Thorleifsson, Lilja Stefansdottir, Stephan Frangakis, Jesse Valliere, Lovemore Kunorozva, Erik Abner, Caleb Ji, Bitten Aagaard, Henning Bliddal, Søren Brunak, Mie T Bruun, Maria Didriksen, Christian Erikstrup, Arni J Geirsson, Daniel F Gudbjartsson, Thomas F Hansen, Ingileif Jonsdottir, Stacey Knight, Kirk U Knowlton, Christina Mikkelsen, Lincoln D Nadauld, Thorunn A Olafsdottir, Sisse R Ostrowski, Ole BV Pedersen, Saedis Saevarsdottir, Astros T Skuladottir, Erik Sørensen, Hreinn Stefansson, Patrick Sulem, Olafur A Sveinsson, Gudny E Thorlacius, Unnur Thorsteinsdottir, Henrik Ullum, Arnor Vikingsson, Thomas M Werge, Chronic Pain Genomics Consortium, FinnGen, DBDS Genomic Consortium, Estonian Biobank Research Team, Genes & Health Research Team, Richa Saxena, Kari Stefansson, Chad M Brummett, Bente Glintborg, Daniel J Clauw, Thorgeir E Thorgeirsson, Frances MK Williams, Nasa Sinnott-Armstrong, Hanna M Ollila, Michael Wainberg
medRxiv 2025.09.18.25335914; doi: https://doi.org/10.1101/2025.09.18.25335914
https://www.medrxiv.org/content/10.1101/2025.09.18.25335914v1

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

2) Schlauch KA, Khaiboullina SF, De Meirleir KL, Rawat S, Petereit J, Rizvanov AA, Blatt N, Mijatovic T, Kulick D, Palotás A, Lombardi VC. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Transl Psychiatry. 2016 Feb 9;6(2):e730. doi: 10.1038/tp.2015.208. PMID: 26859813; PMCID: PMC4872418.

https://www.nature.com/articles/tp2015208

3) Mueth MG, Neufeld P, Michael M, McGrath-Conwell A, Grlickova-Duzevik E, King T, Straub C, Harrison BJ. The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity. Neurobiol Pain. 2025 May 10;18:100184. doi: 10.1016/j.ynpai.2025.100184. PMID: 41089293; PMCID: PMC12516356.
https://pubmed.ncbi.nlm.nih.gov/41089293/

4) Sun W, Wagnon JL, Mahaffey CL, Briese M, Ule J, Frankel WN. Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. J Physiol. 2013 Jan 1;591(1):241-55. doi: 10.1113/jphysiol.2012.240168. Epub 2012 Oct 22. PMID: 23090952; PMCID: PMC3630783.
https://pubmed.ncbi.nlm.nih.gov/23090952/

5) Gao N, Li M, Wang W, Liu Z, Guo Y. The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization. Front Mol Neurosci. 2024 Sep 9;17:1400118. doi: 10.3389/fnmol.2024.1400118. PMID: 39315294; PMCID: PMC11417043.
https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1400118/full

6) Molot J, Sears M, Marshall LM, Bray RI. Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity. Rev Environ Health. 2021 Sep 16;37(4):509-530. doi: 10.1515/reveh-2021-0043. PMID: 34529912.
https://pubmed.ncbi.nlm.nih.gov/34529912/