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Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review)

  • Authors:
    • Fangyan Hu
    • Xiaohua Song
    • Dingxin Long
  • View Affiliations

  • Published online on: October 20, 2021
  • Article Number: 1462
  • Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Calcium (Ca2+) is an essential signaling molecule in all cells. It is involved in numerous fundamental functions, including cell life and death. Abnormal regulation of Ca2+ homeostasis may cause human diseases. Usually known as a member of the transient receptor potential (TRP) family, TRP ankyrin 1 (TRPA1) is the only member of the ankyrin subfamily identified in mammals so far and widely expressed in cells and tissues. As it is involved in numerous sensory disorders such as pain and pruritus, TRPA1 is a potential target for the treatment of neuropathy. The functions of TRP family members are closely related to Ca2+. TRPA1 has a high permeability to Ca2+, sodium and potassium ions as a non‑selective cation channel and the Ca2+ influx mediated by TRPA1 is involved in a variety of biological processes. In the present review, research on the relationship between the TRPA1 channel and Ca2+ ions and their interaction in disease‑associated processes was summarised. The therapeutic potential of the TRPA1 channel is highlighted, which is expected to become a novel direction for the prevention and treatment of health conditions such as cancer and neurodegenerative diseases.

1. Introduction

Calcium ions (Ca2+) are essential electrolytes in the body and have a fundamental role in regulating nerve cell excitation, neurotransmitter release, membrane integrity and muscle contraction. Thus, Ca2+-triggered signalling pathways have an important role in neuron survival, plasticity and nerve transmission.

Over the past decade, transient receptor potential (TRP) channels have attracted increasing attention. TRP ankyrin 1 (TRPA1), a non-selective cation channel permeable to Ca2+ ions, is broadly distributed in various parts of the human body and is associated with various physiological and pathological states, such as sensations of cold and pain, as well as itchiness. Numerous studies have explored the role of the channel in the initiation and development of toxicity. The present review summarized the progress of research on the structure, function and distribution of TPRA1, and discussed diseases related to TPRA1 and Ca2+.

2. TRP family

TRP family members are non-selective cation channels that were discovered in the visual system of the fruit fly Drosophila melanogaster (1). There are 28 known TRP cation channels with different structures and functions (2). All TRP channels have six transmembrane domains (S1-S6), and both N- and C-termini are located on the cytoplasmic side of the cell membrane. These proteins are thought to function as tetramers. TRP channels allow cations such as Ca2+, Mg2+, Na+ and K+ to pass through, which leads to cell depolarisation, influx of extracellular Ca2+, release of Ca2+ from intracellular Ca2+ stores and binding of Ca2+ to calmodulin (CaM), ultimately affecting cell proliferation and apoptosis. The functions of the TRP family are closely related to Ca2+. For instance, TRP cation channel subfamily V member 5 (TRPV5) and TRPV6 are Ca2+ uptake channels in epithelial tissues with unique selectivity for Ca2+ [permeability (P) ratio PCa/PNa >100] (3).

In mammals, there are six TRP channel subtypes according to their amino acid sequence homology: The ankyrin TRP TRPA, the canonical TRPC and TRPV, the melastatin TRP termed TRPM, the polycystic TRP known as TRPP and the mucolipin TRP TRPML (4). Although all TRP channels share certain similarities in sequence and structure, there are significant differences in physiological functions, including cation selectivity, ligand binding and sensitivity to temperature and other environmental conditions among family members (5). The members of TRPV subfamily are considered to be heat sensors, nociceptive sensors, mechano-sensors and osmo-sensors (6,7) and the majority of TRPM subfamily members are implicated in taste, gastric hormone secretion and insulin release (7,8). Brain development and vaso-motor regulation have been reported for the TRPC subfamily channels (7-9), while the defining characteristic of the TRPP subfamily is their association with renal development (7-10). Evidence suggests that the TRPML subfamily is associated with endocytosis and the regulation of autophagy (7-9). The TRPA subfamily has been indicated to function as a thermo-sensor, chemo-sensor and olfactory sensor (6,7). The major physiological function of TRP family members in mammals are listed in Table I.

Table I

TRP family members in mammals.

Table I

TRP family members in mammals.

SubfamilyMain physiological function(Refs.)
TRPVThermo-sensation; nociception; mechano-sensation; osmo-sensation(6,7)
TRPMTaste; gastric hormone secretion; insulin release(7,8)
TRPCBrain development; vaso-motor regulation(7,9)
TRPPRenal development(7,10)
TRPMLEndocytosis and endosomal/lysosomal function; regulation of autophagy(7,9)
TRPAThermo-sensation; chemo-sensing; nociception; olfactory responses(6,7)

[i] TRP, transient receptor potential channel; V, vanilloid; M, melastatin; C, canonical; P, polycystic; ML, mucolipin; A, ankyrin.

Mutations related to human diseases have been detected in nearly 30 members of the TRP channel family, which highlights their importance in human physiology, and they are likely to continue receiving attention in the future.

3. Structure, distribution and physiological function of TRPA1

Ankyrins are a group of linker proteins located on the membrane cytoskeleton that mediate the attachment of intact membrane proteins to spectrin and actin. TRPA1 was first isolated from human fetal lung fibroblasts in 1999(11) and was originally called ankyrin-like with transmembrane domains protein 1(12). It is the only known member of the TRPA subfamily and consists of 119 amino acid residues with a molecular weight of 127.4 kDa.

TRPA1 structure

As all TRP channels, TRPA1 is a tetrameric protein composed of four subunits (119 amino acids) and six transmembrane α-helices (S1-S6), with the pore loop structure located in the hydrophilic region between S5 and 6 (13,14). TRPA1 derives its name from 14-18 ankyrin repeats at the N-terminus (depending on species) in addition to a large number of active cysteine residues (15), which is an unusual structural feature and may be related to its interaction with intracellular components (16).

TRPA1 may be activated by a series of harmful external stimuli and endogenous signals related to cell damage. The latter includes cinnamaldehyde, allicin, allyl isothiocyanate and reactive oxygen species (17,18). The major mechanism of activation is the covalent modification of cysteine and lysine residues at the N-terminus of TRPA1 by highly electrophilic compounds (19). This mechanism promotes local conformational changes, leading to the expansion of the pore loop structure, which increases the permeability to Ca2+. In addition to being activated by reactive electrophiles and oxidants, TRPA1 may also be indirectly activated by the pro-inflammatory factor-mediated phospholipase C signal, in which cytoplasmic Ca2+ are an important regulator of channel gating (20). In addition, as TRPA1 is permeable to both univalent and bivalent cations (including Ca2+, sodium and potassium), it is able to depolarise the membrane and activate Ca2+ signals (21). The structure of TRPA1 is presented in Fig. 1.

TRPA1 distribution

TRPA1 is a non-selective cation channel present in various tissues and organs, but it is mainly expressed in sensory neurons, such as primary sensory neurons in the lung, skin and brain, and peptidergic neurons (22), particularly those in the mammalian dorsal root ganglion, trigeminal ganglion, nodular ganglion and jugular ganglion (23).

In addition, TRPA1 is also present in several non-nerve cells and tissues, including vascular endothelial cells and chondrocytes (24,25), but the function of this expression has remained largely elusive. The major distribution of TRPA1 in the human body is presented in Fig. 2.

Physiological functions of TRPA1

TRPA1 is a cold-sensitive ion channel that may be activated to generate a stress response to endogenous and exogenous chemical stimulation, cold stimulation, mechanical stimulation and various inflammatory mediators. The activation of TRPA1 is closely related to the conduction and generation of cold sensation, the mediation of pain and analgesia, and the regulation of inflammatory substances.

TRPA1 is not mechanically sensitive under physiological conditions, but it may be activated at temperatures <17˚C (26); hence, it serves as a cold-sensitive receptor that detects changes in temperature in the internal and external environment. In addition to mediating temperature sensation and pain (27), TRPA1 functions in mechanical perception (28) and has a role in certain inflammatory states (29). Furthermore, TRPA1 is also associated with hypersensitivity and overexcitation in certain non-neuronal regions and has an important role in the pathophysiology of asthma, neuropathic pain, chronic itching, migraine, gastrointestinal motility disorders, anxiety and cognitive dysfunction (30-34).

Due to its individual characteristics in different organs, TRPA1 has been actively studied as a potential target for treating various diseases.

4. Ca2+ ions

Second messenger is one of the initiating components of intracellular signal transduction. Ca2+, as an ubiquitous second messenger in the cytoplasm, is involved in the regulation of a variety of important physiological processes in cells, such as the synthesis and release of neurotransmitters, regulation of germ cell maturation and fertilization, and regulation of the activities of various enzymes in the body (35). Ca2+ is also closely related to hypertension, coronary heart disease, Alzheimer's disease (AD) and numerous other diseases (36-38). The intracellular second messenger Ca2+ has been a hot research topic in recent years.

The cytosolic free Ca2+ concentration in mammalian cells is generally controlled in the range of 100-200 nmol/l, while the Ca2+ concentration in extracellular organelles is kept in the order of mmol/l (39). The steep but tightly controlled concentration gradient of Ca2+ within and outside the cell membrane, as well as between cytoplasm and organelles, is maintained and dynamically regulated according to cell needs through the cooperative work of a variety of ion channels, ion pumps and transporters (40). The major channels and transporters for intracellular Ca2+ cycling are presented in Fig. 3.

Abnormality of any link may cause instability of Ca2+ homeostasis. Ca2+ homeostasis is essential for cell maintenance; under pathological conditions, Ca2+ homeostasis is altered, with increased cytoplasmic Ca2+ concentrations. Ca2+ channels are a basis for revealing the regulatory laws of Ca2+ homeostasis and vital processes. Certain cation channels, including TRP family members, promote the influx of Ca2+. For instance, although TRPA1 has high permeability to Ca2+, Na+ and K+, it has high Ca2+ selectivity. The PCa/PNa is 6 when the channel opens spontaneously and increases to 9 when the channel is activated by an electrophilic reagent (41).

5. Coupling TRPA1 with Ca2+ ions

TRPA1 mediates Ca2+ internal flow

Compared with most other TRP channels, TRPA1 has higher Ca2+ permeability. The N-terminus of TRPA1 contains two helical Ca2+-binding motifs and the permeation pathway involves two major contraction sites (15), with an aspartate (D918 in mouse, D915 in human) within the pore loop that is critical for Ca2+ permeability (13). Total internal reflection fluorescence and confocal microscopy revealed that the signal generated by Ca2+ influx from a single TRPA1 channel in endothelial cells is at least 200 times that of L-type Ca2+ channels (42). This is because TRPA1 channels exist in the plasma membrane of endothelial cells with a tight binary structure. When one of a pair of channels is opened, afferent Ca2+ is able to bind to the Ca2+-sensitive EF-Hand protein domain at the N-terminus, thereby triggering the adjacent channel (43).

There is a highly conserved structural motif in the TRPA1 channel that is the key site of intracellular Ca2+ elevation caused by Ca2+ storage (44), which explains various Ca2+-dependent processes, including sensitisation, desensitisation and coupling with metabolic receptors. TRPA1-mediated Ca2+ influx is involved in various biological processes such as factor secretion (45) and gene transcription (46). TRPA1 is able to induce apoptosis in cardiomyocytes (47), oligodendrocytes (48) and hippocampal neurons (49) by regulating the Ca2+ concentration. Increasing evidence indicates that TRPA1-mediated Ca2+ influx has a role in determining the pathophysiological state.

Electrical stimulation of TRPA1 in adult mouse cardiomyocytes may lead to activation of the calmodulin-dependent kinase II signalling pathway (45), thereby regulating the availability and manoeuvrability of intracellular Ca2+. TRPA1 is also the major contributor to the increase in Ca2+ in oligodendrocytes caused by ischemia; 70% of the Ca2+ increase may be attributed to TRPA1(50), indicating a key role of the mediation of Ca2+ influx in myelin injury. The molecular basis by which TRPA1 regulates nociceptive neurons is also related to Ca2+; TRPA1 induces local Ca2+ influx at nerve endings, promotes membrane depolarisation and causes the release of neuropeptides from large dense core vesicles through Ca2+-dependent exocytosis, resulting in further amplification of nociceptive sensation, recruitment of immune cells, vasodilation and neurogenic inflammation (51).

Ca2+ regulates TRPA1 activity

Ca2+ ions are the most important endogenous regulators of TRPA1 and they enhance and inhibit the activity of this channel under chemical stimulation. Ca2+ binds to the Ca2+ binding domain at the C-terminus of the molecule, which opens the ion channel. The high permeability of TRPA1 to Ca2+ not only triggers the influx of extracellular Ca2+, but also promotes the release of Ca2+ from intracellular stores, such as the endoplasmic reticulum (52). Ca2+ activation may enhance the responses to other stimuli and desensitise ion channels through a variety of signaling pathways, which in turn regulate the activity of TRPA1.

The opening kinetics of TRPA1 are strongly affected by divalent cations. When Ca2+ binds to the channel, the binding of monovalent cations to the channel is hindered. Under the spontaneous opening state, ~17% of the TRPA1 current is Ca2+ current (41). Ca2+ is able to directly activate TRPA1, which is not only important for the basic reaction of TRPA1 at low Ca2+ concentrations (<1 mM), but may also rapidly inactivate TRPA1 at high Ca2+ concentrations (>1 mM) (53). Therefore, Ca2+ has dual and opposite effects on TRPA1. In addition to direct interaction with TRPA1, indirect interactions occur via cytoplasmic Ca2+ binding proteins, among which CaM is the most prominent. TRPA1 binds CaM to form a Ca2+-sensing channel complex, a key Ca2+ receptor that responds differently to different Ca2+ signals (54). Extracellular Ca2+ activates and/or enhances TRPA1 at low concentrations but quickly inactivates TRPA1 following channel activation. This process is called desensitisation or rapid analgesia (55) and this contrasting effect is the result of Ca2+ regulating TRPA1 through CaM. Both the N- and C-terminal regions may be important for these interactions. A direct effect for Ca2+ on purified human TRPA1 (hTRPA1) independent of CaM has been demonstrated (56); Ca2+ is able to directly activate hTRPA1 and cause structural changes by directly interacting with binding sites other than the N-terminal ankyrin protein repeat domain of hTRPA1.

Furthermore, thermal activation of TRPA1 in chameleon, chicken and rat snake depends on extracellular Ca2+ binding to negatively charged amino acids near the outer surface of channel pore cells, while other divalent cations cannot activate the heat-evoked current (57). Although TRPA1 is a hypothermic receptor, certain researchers assume that harmful hypothermia does not directly activate TRPA1, but rather that the cold environment stimulates the release of intracellular Ca2+ stores (58), activating TRPA1, a Ca2+-dependent ion channel.

6. Interaction between TRPA1 and Ca2+ in disease progression

TRPA1 is a neuronal redox-sensitive Ca2+ internal flow channel that is overexpressed in human cancers. It upregulates Ca2+-dependent anti-apoptosis pathways and promotes resistance to reactive oxygen species (59). Triclosan, an antibacterial agent, was indicated to induce activation of TRPA1 and Ca2+ influx in human prostate cancer stromal cells, resulting in the secretion of VEGF and the growth of prostate cancer epithelial cells (60).

TRPA1 serves as a physiological medium for inflammatory signals and appears to perform a functional role in promoting myoblast migration, fusion and potential activation of human satellite cells. Thus, it may provide a novel target for treating muscle injury or muscle-related diseases via the formation of Ca2+/calmodulin complexes (61).

The inflammatory factor interleukin (IL)-1β increases the functional expression of TRPA1, which leads to Ca2+ overload and a significant decrease in mitochondrial membrane potential. Inhibition of TRPA1 has a protective effect on mitochondrial dysfunction and even apoptosis of rat chondrocytes induced by IL-1β (62). Furthermore, the TRPA1 channel may protect against intestinal fibrosis by mediating Ca2+ mobilisation, in addition to its anti-inflammatory actions (63).

A considerable amount of research has focused on the role of TRPA1 in nervous system regions and suggests that TRPA1 has a promising prospect in both peripheral and central nervous system regions (64-66).

Current therapies of multiple sclerosis mainly focus on pathological immune responses, but they cannot prevent the progression of clinical symptoms (67). TRPA1 regulates the functions of astrocytes by increasing the intracellular Ca2+ concentration (24).

Organophosphate-induced delayed neurotoxicity refers to a series of neurological symptoms that occur within 1-3 weeks after the ingestion of organophosphorus compounds (68). A study from the Shanghai Institute of Pharmacy, Chinese Academy of Sciences, discovered that TRPA1 is the major mediator of delayed neuropathy (69). In the same study, verapamil (an L-type Ca2+ channel blocker that effectively relieves the symptoms of the disease) was indicated to have a neuroprotective role by inhibiting TRPA1-mediated Ca2+ influx.

There is evidence to suggest that excessive Ca2+ in astrocytes may influence synaptic function, and regulating TRPA1 channel activity in astrocytes may provide a novel target for blocking early dysfunction in AD (70).

7. Conclusions and perspectives

After years of in-depth research, TRPA1 has attracted extensive clinical attention due to its function as a chemical sensor for irritation and cell damage, and its relationship with various diseases. For instance, hydrogen sulphide-mediated vasodilation is due to an increase in Ca2+ concentration in trigeminal ganglion neurons activated by TRPA1(71). In addition, TRPA1 is an important subject of toxicology research and is actively studied by pharmaceutical companies (72). However, the functional regulatory mechanisms of TRPA1 remain poorly understood and further investigations may lead to novel protective strategies. In our opinion, areas worthy of further research include the following: i) Unveiling the specific mechanism of the interaction between TRPA1 and Ca2+; ii) exploring the therapeutic potential of TRPA1 in the treatment of pain and airway respiratory diseases through clinical studies; iii) assessing the potential of TRPA1 antagonist as a therapeutic target; and iv) investigating the mechanisms by which TRPA1 regulates Ca2+ in different diseases.


Not applicable.


This work was supported by the National Natural Science Foundation of China (grant nos. 81673227 and 81172712), the Natural Science Foundation of Hunan Province (grant no. 2020JJ4080) and the Key Projects of the Hunan Provincial Department of Education (grant no. 18A254).

Availability of data and materials

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Authors' contributions

FH: Writing-original draft preparation, review and editing. XS: Conceptualization. DL: Supervision, funding acquisition and manuscript revision. Data authentication is not applicable. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



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Hu F, Song X and Long D: Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review). Exp Ther Med 22: 1462, 2021
Hu, F., Song, X., & Long, D. (2021). Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review). Experimental and Therapeutic Medicine, 22, 1462.
Hu, F., Song, X., Long, D."Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review)". Experimental and Therapeutic Medicine 22.6 (2021): 1462.
Hu, F., Song, X., Long, D."Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review)". Experimental and Therapeutic Medicine 22, no. 6 (2021): 1462.