The TRPA1 Ion Channel Mediates Oxidative Stress-Related Migraine Pathogenesis

Abstract

Although the introduction of drugs targeting calcitonin gene-related peptide (CGRP) revolutionized migraine treatment, still a substantial proportion of migraine patients do not respond satisfactorily to such a treatment, and new therapeutic targets are needed. Therefore, molecular studies on migraine pathogenesis are justified. Oxidative stress is implicated in migraine pathogenesis, as many migraine triggers are related to the production of reactive oxygen and nitrogen species (RONS). Migraine has been proposed as a superior mechanism of the brain to face oxidative stress resulting from energetic imbalance. However, the precise mechanism behind the link between migraine and oxidative stress is not known. Nociceptive primary afferent nerve fiber endings express ion channel receptors that change harmful stimuli into electric pain signals. Transient receptor potential cation channel subfamily A member 1 (TRPA1) is an ion channel that can be activated by oxidative stress products and stimulate the release of CGRP from nerve endings. It is a transmembrane protein with ankyrin repeats and conserved cysteines in its N-terminus embedded in the cytosol. TRPA1 may be a central element of the signaling pathway from oxidative stress and NO production to CGRP release, which may play a critical role in headache induction. In this narrative review, we present information on the role of oxidative stress in migraine pathogenesis and provide arguments that TRPA1 may be "a missing link" between oxidative stress and migraine and therefore a druggable target in this disease.

Keywords: TRPA1; calcitonin gene-related peptide; migraine; oxidative stress; reactive oxygen and nitrogen species.

Figure 1

Oxidative stress (OS) in migraine. Oxidative stress may be attributed to external or internal factors, but both result in the overproduction of reactive oxygen and nitrogen species (RONS) that may damage biomolecules. RONS may modulate migraine triggers and lower their thresholds (bold arrow), RONS may damage proteins of the cellular antioxidant defense lowering its efficacy, but on the other hand, migraine is reported to stimulate that system (dotted arrow). Increased energy production or/and demand by migraine susceptible brain leads to overproduction of RONS that may damage the protein of the electron transport chain (ETC) in mitochondria (exclamation mark). Impaired ETC produces more and more RONS (“mitochondrial vicious cycle”). Parts of this figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ accessed on 26 June 2024).

Figure 2

Ribbon representation of transient receptor potential cation channel subfamily A member 1 (TRPA1), which usually functions as a homotetramer. Each monomer is represented with a different color. Taken from the RCSB Protein Data Bank: 3J9P: C.E. Paulsen, J.P. Armache, Y. Gao, Y. Cheng, D. Julius. Structure of the TRPA1 ion channel determined via electron cryo-microscopy. Nature (2015) https://doi.org/10.2210/pdb3J9P/pdb (accessed on 26 June 2024) under the CC0 1.0 Universal (CC0 1.0) Public Domain Dedication.

Figure 3

Structure of transient receptor potential cation channel subfamily A member 1 (TRPA1) channel monomer. TRPA1 monomer contains 6 transmembrane domains, S1–S6, and its N- and C-terminus are embedded in the cytosol. The S5–S6 region forms the central pore and selectivity filter for ions to enter/exit the cell. The N-terminus contains 16 ankyrin repeats and reactive cysteine and lysine residues. Calmodulin (CaM) and Ca²⁺-binding sites are located at the C-terminus. Parts of this figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ accessed on 26 June 2024).

Figure 4

Transient receptor potential cation channel subfamily A member 1 (TRPA1) channel links oxidative stress (OS) with migraine. Oxidative stress resulting from the action of exogenous factors, including migraine triggers or excessive energy production in the migraine susceptible brain, is the source of reactive oxygen and nitrogen species (RONS). TRPA1, represented by its monomer, senses RONS and sends pain signals to sensory neurons, including the trigeminal nerve neurons, essential in migraine pathogenesis. TRPA1 induces the release of calcitonin gene-related peptide (CGRP), a key molecule in migraine. Parts of this figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ accessed on 26 June 2024).