TRP receptors were discovered only about ten years ago. Divided into several subfamilies, TRP receptors govern cellular behavior following a stimulus. Some of them, TRP-A1, TRP-V1 and TRP-M8 receptors are involved in pain transmission and the initiation of migraines. To date, the study of TRP receptors is the most promising lead in the search for new treatments for many diseases (cancer, cardiovascular, asthma, migraine, obesity and neurological diseases.) Here is a summary of the role of TRP receptors in migraine.
Link to video on TRP receptors and their role in migraine
TRP receptors, mediators of pain
Initially identified in 1969 in Drosophila during a study on phototransduction pathways (Cosens et al. 1969), the TRP receptor superfamily. It contains 28 members in mammals, including 27 in humans, which are themselves subdivided into six subfamilies: ankyrin (TRPA), canonical (TRPC), melastatin (TRPM), vanilloid (TRPV), polycystin (TRPP). ), and mucolipin (TRPL) (Li, 2017). Their name TRP (Transient Receptor Potential) comes from the fact that the receptors identified in Drosophila cause a transient depolarization of the cell. Their structure differs essentially at the N-terminal and C-terminal ends, and by the presence or absence of a “TRP box”, a chain of hydrophobic residues whose function is not clearly defined. The transmembrane subunits remain identical.
These chains then assemble into a homotetramer (same receptor subfamily) or heterotetramer (between several subfamilies) to form a non-cation-selective transmembrane channel (Schaefer et al. 2005; Staruschenko et al. 2010; Vassort et al. . 2008). Their locations on the membrane of cells of almost all types of tissues allow them to be sensors of the environment external to the body, but also of the extracellular environment of the organism. The transmembrane channel can also be found in the intracellular environment, in the lipid membrane of the cell's organelles such as lysosomes, the Golgi apparatus, the endoplasmic reticulum or synaptic vesicles (Gees et al. 2010). Activated at the level of the organelles, they essentially act as calcium channels while at the level of the cell membrane, their activation generates a depolarization of the cell, a consequence of the activation or inactivation of voltage-gated channels and the modulation of their ion flux (Kumamoto et al. 2016).
TRPV2-4 receptors; TRPM8
TRPV2-4
In addition to TRPV1, the presence of TRPV2, TRPV3 and TRPV4 within the trigeminal fibers that project to the dura mater was found. So far, TRPV2 and TRPV3 have not shown any real involvement in the pathophysiology of migraine (Rainero et al. 2013). TRPV4 has been identified as a mechanoreceptor and an osmo-receptor (Wei et al. 2011) and is believed to be present on 50% of meningeal afferents. Indeed, it is the proportion of fibers that is activated by 4α-Phorbol, a TRPV4 agonist. Furthermore, topical application of this agonist to the dura mater causes cephalic allodynia which can be blocked by a TRPV4 antagonist (Everaerts et al. 2010). The authors hypothesized that its activation could be the cause of the pulsatile character of the pain. The use of a TRPV4 antagonist in the treatment of migraines has not been explored beyond the preclinical phases, mainly because of the significant side effects it causes: dryness of the mucous membranes, constipation, visual disturbances, deterioration cognitive and even headaches (Everaerts et al. 2010).
TRPM8
The TRPM8 receptor also seems to be of interest in the pathophysiology of migraine for several reasons. First, this receptor presents a genetic particularity characterized by a single nucleotide polymorphism (PSN), where the cytosine base (C) is replaced by a thymine (T) at position chr2: 234835093 (Dussor et al. 2016). The expression of this PSN varies across the planet depending on latitude (Key et al. 2018). Humans carrying the T:T allele have a higher risk of developing migraines compared to the C:C or C:T alleles (Chasman et al. 2011) . The frequency of expression of the T allele is only 5% in a population native to Nigeria, while it is 88% in Finland. Its expression in Southeast Asia is 48% for the C:C variation and 36% for the C:T variation. Thus, the frequency of the T allele appears to match the latitude of the region, suggesting that populations living in the north are predisposed to developing a specific TRPM8 variant. The particular expression of this variant may respond differently to cold exposure, and lower activity in cold climates could allow for better adaptation to this environment. Although this hypothesis is not confirmed, the expression of the T allele (higher in cold climates and lower in warm climates) corresponds with the epidemiology of migraine, where the prevalence is higher in Europe, lower in Africa and intermediate in Asia. Second, cold headaches, caused for example by the rapid ingestion of cold drinks, also called “ice cream” headaches, have been shown to be the consequence of direct activation of TRPM8 and, unlike headaches of inflammatory origin, are reduced by its inhibition (Dussor et al. 2016; Kayama et al. 2018). There are menthol patches to apply to the forehead and temples to relieve migraines, but the results have never been scientifically proven. Third, this receptor is predominantly expressed in the trigeminal ganglion compared to the dorsal root ganglia. Finally, it is co-localized with the TRPV1 receptor, and only in neurons of the trigeminal system (Kobayashi et al. 2005). Interestingly, an in vitro study showed that TRPM8 activation was able to inhibit TRPV1 function, where they are co-expressed (Kayama et al. 2018). Despite these arguments in favor of a role of TRPM8 receptors in migraine, there is still uncertainty about the activation of TRPM8 in the meninges during a headache, and recent studies sometimes show an increase in its expression ( Burgos-Vega et al. 2016), or a reduction thereof. (Ren et al. 2015). It is in this context that the pharmaceutical manufacturer AMGEN decided to test its TRPM8 antagonist, AMG2850, in a preclinical study. Published in 2015, the results concluded that there was a lack of effectiveness in the prophylactic treatment of migraine (Lehto et al. 2015).
A. The ankyrin 1 receptor
Introduction
The transient receptor potential receptor ankyrin 1 (TRPA1) is expressed notably in all cell types as well as in nociceptive fibers. It is often described as a chemical environmental sensor, and many of its activators are present in our environment every day. The majority of them induce inflammation and pain (Talavera et al. 2020), making TRPA1 the target of new anti-inflammatories and analgesics. Thus TRPA1 seems to play a fundamental role in the development and maintenance of pain (Meents et al. 2019). Just like the other TRP receptors, whose studies are very recent, TRPA1 was cloned for the first time in 1999 (Jaquemar et al. 1999). We are therefore still at the beginning of understanding the physiological role and the therapeutic interest presented by these receptors. Recently, the cryomicroscopy study allowed a more precise analysis of the structure of TRPA1 (Paulsen et al. 2015).
The role of TRPA1 in inflammation
TRPA1 and TRPV1 receptors are sensitive to the release of neuropeptides and variations in calcium concentration caused during inflammation. The PIP 2 protein that we described previously also plays a fundamental role in the regulation of TRPA1 and TRPV1. During inflammation, it degrades into diacylglycerol (DAG) and inositol triphosphate (IP3), capable of activating receptors by activating PKC, forming lipid oxidative derivatives and/or by cytosolic calcium mobilization ( Mizumura et al. 2009). These receptors are also sensitized by inflammation mediators, such as growth factors, proteases, bradykinin or certain cytokines. Thus, in the trigeminal ganglion, NGF increases the expression of TRPA1 mRNA via the p38 MAPK signaling pathway, a pathway essentially activated in response to cellular stress or an inflammatory state (Diogenes et al. 2007). Their presence in both neuronal and non-neuronal cells places them at the center of the inflammatory mechanism. They modulate the activity and cellular response responsible for maintaining inflammation, but are also regulated by calcium and the activity of many other proteins (Bautista et al. 2013).
These inflammatory mediators cause progressive sensitization of the TRPA1 receptor and thus modulate its activity (Malin et al. 2011). TRPA1 also plays a role in modulating the expression of many genes involved in inflammation. Around 2000 genes are likely to be influenced by TRPA1 activation, particularly genes encoding cytokines, membrane receptors, interleukins, growth factors or cells of the immune system (Wilson et al. 2013). Recently, De Logu's team provided a better understanding of the inflammatory mechanism mediated by TRPA1 during neuropathic pain (De Logu et al. 2017). To do this, they focused on Schwann cells and showed that not only do these cells express TRPA1, but that it is activated by oxygenated derivatives released by macrophages. Indeed, the extravasation caused during inflammation stimulates macrophages which, through their NOX2 receptors, release ROS.
The latter specifically target the TRPA1 receptors of Schwann cells which, via their NOX1 receptors, will in turn release other oxygenated derivatives. This new release will be two-way: the ROS will both stimulate the macrophages more intensely and activate the TRPA1 receptors present in the neuronal cell. Progressively, sensitization of the receptor at the level of the neuron leads to the onset of allodynia, stimulates the release of inflammatory proteins and leads to the maintenance of inflammation.
TRPA1
TRPA1 in migraine
The involvement of TRPA1 in migraine is not only strongly suggested by its sensitivity to exogenous and endogenous agents, known to trigger attacks, but also by the decrease in its expression when treatment is administered (Benemei and Dussor, 2019). . It seems that in the context of migraine, stimulation of TRPA1 occurs at the level of afferent sensory fibers of the dura mater (Huang et al. 2012). While natural compounds are capable of initiating a migraine attack by activating TRPA1, certain plants are known for their anti-migraine and anti-inflammatory effects. This is the case, for example, of butterbur, whose main constituents, petasin and isopetasin, are capable of desensitizing TRPA1 (Benemei et al. 2017). Another plant, tanacetum parthenium from the same Asteraceae family, has an active component, parthenolide, also capable of desensitizing the receptor.
After an initial moderate activation, parthenolide gradually initiates persistent desensitization of the receptor. At the level of the meningeal trigeminal fibers, this desensitization prevents the release of CGRP, even after strong stimulation of the receptor by its agonist AITC (Materazzi et al. 2013). There is still a long way to confirm the mechanism of TRP receptor activation and inhibition. The better they are understood, the easier it will be to develop specific treatments capable of modulating their activity in a targeted manner for certain pathologies.
Interaction between TRPV1 and TRPA1
The properties of the TRPA1 channel can also be modulated by its co-expression with TRPV1. Isolated, the ratio between conductance measured at positive and negative potentials is 1.5 for TRPA1, whereas in cells where it co-expresses with TRPV1 it increases to 2.4 (Staruschenko et al. 2010). As a result, the co-expression of these receptors increases the probability of membrane depolarization, and therefore the possibility of generating an action potential. Other studies show that not only does the activity of one influence that of the other, but that it is also possible to obtain, under certain conditions, heterodimerization. The formation of this TRPV1-A1 complex leads to a new channel with biophysical and biochemical properties of its own and distinct from those of the original channels. (Sadofsky et al. 2014). The co-expression of TRPA1 and TRPV1 is not found in all tissues, but mainly in the skin (keratinocytes) and sensory neurons (Kobayashi et al., 2005).
Under normal conditions, TRPA1 expression is observed in approximately 55% of TRPV1-positive neurons (Diogenes et al. 2007), but in the presence of NGF it increases to 80%.
Patil and his colleagues show that the action of protein kinases A and C is different depending on the type of sensory neurons (peptidergic, non-peptidergic or LTMR), and depending on the expression of the receptors (only one of the receptors or both) (Patil et al. 2020). Thus, peptidergic neurons expressing both TRPA1 and TRPV1 are sensitive only to PKC. In contrast, non-peptidergic neurons, which do not express TRPV1, are not sensitive to any of the kinases. Neurons that express TRPV1 strongly and TRPA1 weakly are sensitive to kinases only under inflammatory conditions. There are thus several factors influencing receptor sensitization. It also seems that this mechanism involves other mediators found in the inflammatory environment: particularly NGF, bradykinin or prostaglandin E2, which also influence the sensitization of the two receptors in different ways depending on the subgroups of neurons. Note that peptidergic neurons which only express TRPA1 are not sensitive to inflammation and only convey neuropathic pain. The TRPA1-TRPV1 heterodimer therefore appears to be specific to the inflammatory response (Patil et al. 2020).
This physical interaction is essentially possible thanks to the transmembrane protein 100 (Tmem100). In mice with a deficiency of this protein, the TRPA1-TRPV1 complex is almost no longer found in the sensory neurons. These mice also show a reduction in mechanical hyperalgesia induced by inflammation, again showing the importance of the formation of this complex to convey inflammatory pain. (Weng et al. 2015; Weyer et al. 2015). The idea that the co-expression of TRPV1 and TRPVA1 is present essentially at the level of sensory neurons is of major interest in the development of new treatments against pain. One possibility considered by many laboratories would be to target the heterodimer; however, its characterization is still limited and no molecule has been proposed yet. The second possibility would be to develop agonists specific for one or the other, but whose action would be potentiated by their co-expression. This is the case, for example, of the cannabinoid agonist AM1241 which specifically targets TRPA1, but which is five times more effective when it is co-expressed with TRPV1 (Akopian et al. 2008). Likewise, capsazepine (CPZ), a specific TRPV1 antagonist, can potentiate the response of the AITC agonist on TRPA1. This shows us that there is a close relationship in the functioning of these two receptors, and that a specific antagonist of the heterodimer is quite possible. In a pharmacological development, it will however be necessary to ensure that the antagonist is very specific to the complex and does not intervene in the proper functioning of the channels alone.
When the heterotetramer is not formed, the homotetramers manage to influence each other. The mechanism is still a highly debated subject. It seems that this activity is dependent on numerous proteins, more particularly phospholipases and kinases, released massively during inflammation. One of the possible mechanisms involves the depletion of the phospholipid PIP 2 in an inflammatory environment as well as an increase in phospholipase C which would cause sensitization of the TRPA1 channel. The massive entry of calcium into the cell and the presence of calmodulin would then allow the sensitization of TRPV1. Conversely, desensitization phenomena can be observed. Indeed, cross-desensitization between specific agonists of these receptors has been observed. AITC, through a calcium-dependent phenomenon, can desensitize TRPV1 (Ruparel et al. 2008a). The calcium influx into the neuron activates calcineurin which will then dephosphorylate and desensitize TRPV1. This same mechanism has notably been found with the cannabinoid AM1241. (Akopian et al. 2009; Patwardhan et al. 2006). Similarly, desensitization of TRPA1 by capsaicin has been reported (Ruparel et al. 2008b).
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