TRP channels in health and disease at a glance

The transient receptor potential (TRP) protein was first designated in the 1960s as the underlying mediator of impaired visual adaptation in Drosophila, where photoreceptors carrying mutations of the trp gene exhibit a transient voltage response to continuous light illumination (Cosens and Manning, 1969; Minke, 1977; Montell et al., 1985). The trp gene in Drosophila was cloned in the 1980s using positional cloning (Montell and Rubin, 1989), and its function as a receptor-operated cation channel in photoreceptors was demonstrated in 1992 (Hardie and Minke, 1992). Since the 1990s, homology cloning has been used to clone TRP genes (Wes et al., 1995; Zhu et al., 1995), leading to the discovery of TRP channels in various organisms, including 17 TRP genes in Drosophila and Caenorhabditis elegans, and 28 TRP genes in mammals (Nilius and Owsianik, 2011).

Since the late 1990s, the molecular cloning of mammalian TRPs, in combination with heterologous overexpression and targeted mouse gene inactivation approaches, has brought significant advances in characterization of the unique features of TRP channels and understanding of their functions (Clapham, 2003; Nilius and Szallasi, 2014; Zhang et al., 2018) (see poster). Unlike other ion channels, the polymodal activation features of TRPs, such as activation by endogenous ligands or various environmental stimuli, confer diverse physiological and pathological roles. TRPs are non-selective cation channels with a wide spectrum of relative permeability to Ca²⁺ versus Na⁺ (P_Ca/P_Na), ranging from 0 to 100 (see poster) (Owsianik et al., 2006). Mutagenesis studies have mapped the residues in the pore region responsible for the high selectivity for Ca²⁺. Further detailed analyses of Ca²⁺ selectivity, structure–function relations and gating mechanisms have benefitted from a recent revolutionary breakthrough in single-particle cryo-electron microscopy (cryo-EM), highlighting a new era in the study of TRP structural biology (see poster). Since the first report of the TRPV1 structure at 3.4 Å (0.34 nm) resolution using cryo-EM in 2013 (Liao et al., 2013), there has been a rapid increase in the number of TRPs whose atomic structure has been resolved at even higher resolutions (Madej and Ziegler, 2018; Vangeel and Voets, 2019; Zhang et al., 2018). These atomic-resolution structures have provided novel insights into the assembly, gating, permeation and regulatory mechanisms of TRP channels, which will undoubtedly accelerate the design and development of novel therapies for TRP-related diseases.

Here, we briefly discuss the structure–function relations of TRP channels, which include general and unique features, the structural bases of Ca²⁺ permeation and gating, and the sensing and decoding of environmental cues and cellular stimuli. We also summarize the physiological and pathological functions of TRP channels. Recent advances in the atomic-resolution structures of TRP channels may lay the framework for the development of therapies for various diseases associated with TRP channel dysfunction.

Based on sequence homology, the 28 mammalian TRP channels are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA1, TRPP and TRPML (Clapham, 2003). These subfamilies can be separated into two groups based on sequence and topological differences: group I comprises the TRPC, TRPV, TRPM and TRPA1 subfamilies, all of which have a large cytosolic domain, whereas group II comprises the TRPP and TRPML subfamilies, both of which have a large exoplasmic domain (Venkatachalam and Montell, 2007).

Although TRP channels share a common overall architecture of six transmembrane (TM) domains (S1–S6) and a central pore loop linking S5 and S6, their intracellular N- and C-termini vary considerably (Montell, 2005). There are variable numbers of ankyrin repeats at the N terminus of TRPCs (which have 3 or 4 repeats), TRPVs (6 repeats) and TRPAs (14 or 15 repeats), which are implicated in protein–protein interactions, trafficking and gating, whereas the N terminus of TRPM proteins is characterized by four stretches of residues designated as the TRPM homology domain (MHD). At the C terminus, TRPCs, TRPVs and TRPMs contain a conserved TRP domain, which has been implicated in channel gating or coupling between different channel domains and is important for allosteric modulation (Vangeel and Voets, 2019). Uniquely, TRPM6 and TRPM7 have an atypical α-kinase domain at the C terminus (Nadler et al., 2001; Runnels et al., 2001), whereas TRPM2 has a NUDT9 nudix hydrolase (NUDT9-H) domain (Perraud et al., 2001), which functions as a putative ADP-ribose (ADPR) pyrophosphatase (Iordanov et al., 2019).

TRPs form homo- or hetero-tetrameric channels with subunits from the same subfamily. TRPP1 (also known as PKD2), however, forms heterotetramers with one subunit comprised of the last six TM domains (S6–S11) of the 11 TM domain-containing PKD1 (Hardy and Tsiokas, 2020) at a stoichiometry of 3:1 (PKD2:PKD1; Su et al., 2018). Different TRP channels have different current–voltage (I–V) relations, including inward-rectifying, outward-rectifying and linear I–V relations, which determine whether they make it easier for ions to move into or out of the cell (see poster). For some TRP channels, the I–V relations may vary depending on the degree of activation. The single-channel conductance of different TRP channels ranges from 10 to 100 pS (Clapham, 2003).

The architecture of TRPs (see poster) contains a pore loop for ion conduction, which is surrounded by the S1–S4 domains, and the voltage-sensing-like domain (VSD-L). The S4–S5 linker connecting the pore domain and VSD-L play an essential role in channel gating (Zhang et al., 2018). Although the VSD-L does not have a canonical voltage sensor, it is involved in the formation of binding sites for TRP agonists such as Ca²⁺ (in TRPM2, TRPM4 and TRPM8), phosphatidylinositol (4,5)-bisphosphate (PIP₂), menthol and icilin (in TRPM8) (Huang et al., 2020). These organized domains assemble into the three or four layers of TRP architecture: a layer consisting of the extracellular domain, a layer consisting of the TM domains and one or two layers consisting of the cytosolic domain (CD) (Huang et al., 2020).

As Ca²⁺-permeable, non-selective cation channels, TRPs exhibit a wide range of relative permeability to Ca²⁺ versus monovalent cations (P_Ca/P_Na or P_Ca/P_K, with higher numbers indicating higher Ca²⁺ selectivity; Owsianik et al., 2006). Two members of the TRPM subfamily, TRPM4 and TRPM5, are virtually Ca²⁺ impermeable (P_Ca/P_Na<0.01), whereas TRPV5 and TRPV6 are highly Ca²⁺ selective (P_Ca/P_Na>100). TRPs are permeable not only to abundant physiological cations, but also to trace metal cations such as Zn²⁺ and Fe²⁺ (Bouron et al., 2015).

The selectivity filter of TRPs is located at the upper part of the ion-conducting pore (see poster; the representative pore structures of TRPM4, TRPV1 and TRPV6 are adapted with permission from Vangeel and Voets, 2019, copyright Cold Spring Harbor Laboratory Press). Early mutagenesis studies have established that the negatively-charged aspartate and glutamate residues in the pore loop are critical for divalent cation permeation and selectivity (Owsianik et al., 2006). Recent structural analyses have provided the atomic mechanisms for Ca²⁺ selectivity. The selective filter domain contains the amino acid sequence TIGMG[D/E] in TRPV1–TRPV4 (Deng et al., 2018), FGE in TRPM7 (Duan et al., 2018b), FGQ in TRPM4 (Duan et al., 2018c), LGD in TRPPs (Shen et al., 2016), GLIN in TRPC4 and TRPC5 (Duan et al., 2018a, 2019), FGN in TRPM2 (Iordanov et al., 2019), LGD in TRPA1 (Suo et al., 2020), NGDD in TRPMLs (Chen et al., 2017; Fine et al., 2018; Hirschi et al., 2017) and TIID in TRPV6 (Saotome et al., 2016). Like TRPV5 and TRPV6 (Dang et al., 2019; Hughes et al., 2018; Singh et al., 2018), most non-selective TRPs have negatively-charged amino acid residues in the selective filter domain. However, the key difference between TRPV5 and TRPV6 and the other TRPs is that the side chain of the negatively charged aspartate residue of TRPV5 and TRPV6 is located at the narrowest part of the pore, leading to an extremely strong binding for Ca²⁺ and a small interatomic distance at the outer channel pore to form a narrow constriction (Saotome et al., 2016). In contrast, the negatively charged residues of other TRPs are not located at the narrowest part, creating a much weaker binding site for Ca²⁺, and hence low values of P_Ca/P_Na (Huynh et al., 2016; Liao et al., 2013; Paulsen et al., 2015; Zubcevic et al., 2016).

Localized at the plasma membrane or intracellular organelles (Zhang et al., 2018), TRPs are activated by a wide variety of extra- and intra-cellular stimuli (Box 1) (Clapham, 2003). Several TRPs are sensitive to thermal transitions. For example, TRPV1–TRPV4, TRPM2 and TRPM3 are sensitive to warmth or noxious heat, whereas TRPM8, TRPA1 and TRPC5 are activated by cooling or by noxious cold temperatures (Bamps et al., 2020; Buijs and McNaughton, 2020; Dhaka et al., 2006; Tan and McNaughton, 2018). The thermal sensing mechanisms of TRPs are yet to be fully understood (Baez et al., 2014; Singh et al., 2019). Activation of TRPC channels is mediated by the phospholipase C (PLC) pathway, either directly through diacylglycerol (DAG) for TRPC2, TRPC3, TRPC6 and TRPC7, or indirectly through cooperative PLCδ activity and G_i/o stimulation for TRPC4 (Hofmann et al., 1999; Thakur et al., 2016; Venkatachalam et al., 2003). Activation of TRPV5 or TRPV6 requires PIP₂ binding to a pocket formed by the N-linker, which is located between the pre-S1 and ankyrin repeat domains and features a helix-turn-helix motif (Pumroy et al., 2020), the S4–S5 linker and the S6 helix (Hughes et al., 2018; Singh et al., 2018). Moreover, calmodulin (CaM) is associated with the C terminus of TRPV5 and TRPV6, blocking the channel gate at high intracellular Ca²⁺ concentrations ([Ca²⁺]_i) (Hughes et al., 2018; Pumroy et al., 2020; Singh et al., 2018). In epithelial cells, TRPV6 is constitutively active in vivo (Xin et al., 2019).

Whereas a rise in [Ca²⁺]_i inactivates TRPV5 and TRPV6, it activates TRPM4, TRPM5, TRPM2 and TRPA1. A Ca²⁺-binding site coordinated by the amino acid sequence EQND, first described as being close to the S3 helix in TRPM4 (Autzen et al., 2018), is also present in TRPM2 and TRPM8 (Huang et al., 2018, 2019; Yin et al., 2019a). Moreover, an ATP-binding site is present at the interface between the MHR1/2 domain and the adjacent MHR3 domain in TRPM4, but not in TRPM5 (Guo et al., 2017), resulting in ATP-mediated inhibition of Ca²⁺-induced currents only in TRPM4.

Activation of TRPM2 requires ADPR binding to the C-terminal NUDT9-H domain (Csanady and Torocsik, 2009; Kuhn and Luckhoff, 2004). Interestingly, recent cryo-EM structures of TRPM2 have revealed an additional ADPR-binding site, which is located in the MHR1/2 domain (Huang et al., 2018; Wang et al., 2018). Binding of ADPR causes a series of conformational changes preceding channel opening of TRPM2 (Huang et al., 2018; Yin et al., 2019b).

TRPM6 and TRPM7 activation requires PIP₂ and the lowering of internal Mg²⁺ concentration (Nadler et al., 2001; Runnels et al., 2002; Voets et al., 2004; Xie et al., 2011). The function of these channels is regulated by intracellular concentrations of ATP and other nucleotides (Demeuse et al., 2006; Ferioli et al., 2017; Zhang et al., 2014). PIP₂ is also crucial for TRPM8 activation, through binding to an interfacial cavity that is formed by the S4–S5 linker and the top layer of CD, assembled by the pre-S1 domain, the S4–S5 junction, the TRP domain and the MH4 domain from the neighboring subunit (Yin et al., 2019a; Yin and Lee, 2020). Binding of PIP₂ allosterically enhances the effects of other cooling agonists, such as menthol, producing synergistic activation of TRPM8.

For group II TRPs, PIP₂ is required for TRPML activation (Shen et al., 2012; Zhang et al., 2012), but negatively regulates TRPP2 and TRPP3 (Zheng et al., 2018). The cryo-EM structures of TRPML1 (also known as MCOLN1) reveal that binding of PI(3,5)P₂ to the extended helices of S1, S2 and S3 causes the S4–S5 linker to move, thereby allosterically opening the channel (Chen et al., 2017; Fine et al., 2018; Schmiege et al., 2017).

TRPs act as multifunctional cellular sensors (Clapham, 2003; Zhou et al., 2020) by integrating a plethora of external and internal signals and converting them to physiological and pathological responses (Wu et al., 2010a). Dysfunction of TRP channels causes various inherited and acquired diseases (see poster; Box 2).

Several TRPs, including TRPC6, TRPV4, TRPV3, TRPM1, TRPM3, TRPM4, TRPM6, TRPM2, TRPM7, TRPA1, TRPML1 and TRPP1, have been linked to genetic diseases (Nilius and Owsianik, 2010). Numerous single-nucleotide polymorphisms (SNPs) have also been identified in TRP channels, although their roles in causing disease are not well established.

Mutations in TRPC6 are linked to a human proteinuric kidney disease called focal and segmental glomerulosclerosis (FSGS) (Reiser et al., 2005; Riehle et al., 2016; Winn et al., 2005). Both gain-of-function (GOF) and loss-of-function (LOF) mutations of TRPC6 may contribute to FSGS (Hofstra et al., 2013; Nilius and Owsianik, 2010; Riehle et al., 2016). Although it is still unclear how TRPC6 contributes to the development of FSGS, defects in the permeability barrier function in the glomeruli of FSGS patients may cause proteinuria and progressive kidney failure. Moreover, a functional SNP that causes upregulation of TRPC6 has been associated with idiopathic pulmonary artery hypertension (PAH) (Yu et al., 2009).

Mutations in TRPV4 have been identified in patients with various neurodegenerative disorders, such as Charcot–Marie–Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy (SPSMA), distal spinal motor neuropathy, distal spinal muscular atrophy (SMA) (Auer-Grumbach et al., 2010; Deng et al., 2010; Fiorillo et al., 2012; Lamande et al., 2011; Landoure et al., 2010), and severe intellectual disability and neuropathy (Thibodeau et al., 2017). Mutations in TRPV4 also cause other disorders, including various skeletal dysplasias, ranging from mild autosomal dominant brachyolmia to severe metatropic dysplasia (MD) (Nilius and Voets, 2013; Toft-Bertelsen and MacAulay, 2021), arthropathy (Lamande et al., 2011; McNulty et al., 2015), arthrogryposis (Velilla et al., 2019) and progressive osteoarthropathy (Lamande et al., 2011; Nishimura et al., 2012). The majority of these disease-causing TRPM4 mutations are GOF mutations (Nilius and Voets, 2013), whereas some are LOF mutations (Lamande et al., 2011). Moreover, there are genotype–phenotype overlaps, as some mutations, such as A217S, E278K, V620I and P799R, are involved in both skeletal and neurological disorders (Toft-Bertelsen and MacAulay, 2021).

GOF mutations of TRPV3 cause Olmsted syndrome (OS), a rare keratinization disorder (Duchatelet et al., 2014; Eytan et al., 2014; He et al., 2015; Lin et al., 2012; Ni et al., 2016). Moreover, patients carrying G573A mutations in TRPV3 have multiple immune dysfunctions (Danso-Abeam et al., 2013). TRPV3-associated OS can be effectively treated by the epidermal growth factor receptor (EGFR) inhibitor erlotinib (Greco et al., 2020), due to cross-activation of TRPV3 and EGFR (Cheng et al., 2010).

Mutations of TRPM1 cause congenital stationary night blindness (CSNB) (AlTalbishi et al., 2019; Lee et al., 2020; Nilius and Owsianik, 2010; Zhou et al., 2016) due to a loss of function of the ON bipolar neurons that are postsynaptic to the rod and cone photoreceptors, as evident from electroretinography (ERG). Consistent with this, a loss of ON bipolar cell response as characterized by ERG is also observed in Trpm1-knockout mice (Koike et al., 2010; Morgans et al., 2009).

GOF mutations of TRPM3 have recently been identified as the cause of developmental and epileptic encephalopathies (DEE) (Dyment et al., 2019; Van Hoeymissen et al., 2020). In HEK293T cells heterologously overexpressing TRPM3, DEE-causing mutations, such as V990M and P1090Q, result in increased basal activity, enhanced sensitivity to pregnenolone sulfate and heat, and reduced sensitivity to inhibition and inactivation. Moreover, mutations of TRPM3 (I65M and I8M) have been linked with inherited forms of early-onset cataracts, and knockin mice expressing the I65M mutant form of human TRPM3 recapitulate human cataract development (Bennett et al., 2014; Zhou et al., 2021).

Since the first TRPM4 mutation (E7K) was identified in patients with progressive familial heart block type 1 (PFHB1) (Kruse et al., 2009), many GOF or LOF mutations have been found in patients with various forms of cardiac conduction defects (CCD) (Liu et al., 2010; Stallmeyer et al., 2012) and in patients with Brugada syndrome (BrS) (Liu et al., 2013). Moreover, TRPM4 mutations have been found in childhood cases of CCD and arrhythmia (Bianchi et al., 2018; Syam et al., 2016), as well as in patients with hypoplastic right heart (Reuter et al., 2020).

LOF mutations of TRPM6 cause familial hypomagnesaemia with secondary hypocalcaemia (HSH) (Schlingmann et al., 2007). Both intestinal absorption and renal re-absorption of Mg²⁺ are defective in HSH patients (Chubanov et al., 2007; Nilius and Owsianik, 2010).

SNPs of TRPM2 and TRPM7 have been identified in a subset patients with Guamanian amyotrophic lateral sclerosis (ALS-G) and Parkinsonism-dementia complex of Guam (PDC-G) (Hermosura et al., 2005, 2008; Hermosura and Garruto, 2007), although the causality remains to be established (Hara et al., 2010). LOF mutations in TRPM7 may be associated with inherited macrothrombocytopenia (Stritt et al., 2016).

A GOF mutation of TRPA1, N855S, is linked to familial episodic pain syndrome (FEPS) (Kremeyer et al., 2010; Nilius and Szallasi, 2014). Moreover, some SNPs of TRPA1 may be associated with defects in heat or cold sensation (Binder et al., 2011; Kim et al., 2006; Naert et al., 2020).

LOF mutations in TRPML1 result in an autosomal recessive neurodegenerative lysosomal disorder, type IV mucolipidosis (ML-IV) (Wang et al., 2014).

Mutations in TRPP1 (PKD2) and PKD1 account for 15% and 85% of autosomal dominant polycystic kidney disease (ADPKD), respectively (Audrezet et al., 2012, 2016). ADPKD is characterized by the progressive development of large epithelium-lined cysts in the kidney, liver, pancreas, seminal tract and arachnoid membrane (Nilius and Szallasi, 2014). ADPKD also causes cardiovascular abnormalities, such as small artery aneurysms in the heart and brain (Dietrich et al., 2006) and defective septum formation of the heart, which is caused by TRPP1 mutations (Wu et al., 2000).

TRP channels are ubiquitously expressed and are involved in diverse physiological and pathological functions (see poster). Extensive research using genetically modified animal models and pharmacological agents has provided strong evidence to substantiate TRPs as therapeutic targets for various diseases.

Several TRPs are abundantly expressed in the brain. Knockout of Trpc3 in mice causes a deficit in metabotropic glutamate receptor-dependent synaptic transmission (Hartmann et al., 2008), suggesting an important role of TRPC3 in this process. Loss of TRPC1, TRPC4 and TRPC5 has also been shown to cause synaptic depression (Schwarz et al., 2019). Activation of TRPC1, TRPC4 and TRPC5 produces detrimental effects in ischemic stroke (Jeon et al., 2020), whereas activation of TRPC6 produces beneficial effects in ischemic stroke (Shekhar et al., 2021). Deletion of Trpc5 or Trpc4 results in reduced innate fear in mice (Riccio et al., 2009, 2014). Moreover, overactivation of TRPM2 and TRPM7 is involved in ischemic stroke (Alim et al., 2013; Ye et al., 2014), and these proteins are considered therapeutic targets for ischemic brain injury (Belrose and Jackson, 2018; Lin and Xiong, 2017).

Several thermosensitive TRPs, including TRPV1, TRPM2, TRPM3, TRPM8 and TRPA1, are expressed in nociceptive sensory neurons (Julius, 2013; Voets et al., 2019). Knockout of Trpv1 impairs but does not abolish thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000), whereas knockout of Trpm3 (Alkhatib et al., 2019; Su et al., 2021; Vriens et al., 2011) or triple knockout of Trpv1, Trpm3 and Trpa1 can fully eliminate acute noxious heat sensing in mice (Vandewauw et al., 2018). TRPV1, TRPV3, TRPA1 and TRPM8 have been pursued as analgesic targets to treat cluster headaches, ocular pain, neuropathic pain, diabetic peripheral neuropathic pain, osteoarthritis, overactive bladder disorder, inflammatory pain and cancer pain (Kaneko and Szallasi, 2014). Moreover, TRP channels such as TRPA1, TRPV1, TRPV3 and TRPV4, which are expressed in the nociceptive neurons and skin tissue-resident cells, are involved in itching (Feng et al., 2017; Kittaka and Tominaga, 2017; Wilson et al., 2011; Xie and Hu, 2018).

Multiple TRPs are associated with cardiovascular diseases (Hof et al., 2019). TRPC1, TRPC3, TRPC4, TRPC6, TRPC7 and TRPM4 are involved in cardiac hypertrophy and heart failure in mouse models (Freichel et al., 2017). Whereas TRPV2 is essential for maintaining cardiac structure (Katanosaka et al., 2014), the role of TRPM2 in ischemic heart injury has been controversial (Hiroi et al., 2013; Miller et al., 2013). Both TRPM7 and TRPP1 are required for embryonic heart development (Sah et al., 2013; Wu et al., 2000). Several TRPs, including TRPM4, TRPC3, TRPC6 and TRPM7, have been implicated in cardiac arrhythmia. Moreover, TRPs that are expressed in endothelial and smooth muscle cells, such as TRPV1, TRPV4, TRPC6, TRPM4 and TRPP1, contribute to vascular pathologies, including pulmonary hypertension, subarachnoid hemorrhage and aneurism (Yue et al., 2015).

Because of its stimulation by environmental irritants and inflammatory stimuli, TRPA1 plays a role in chronic asthma and chronic obstructive pulmonary disease (COPD), and TRPV1 also plays a role in asthma as well as in chronic cough (Belvisi and Birrell, 2017). TRPM8 may exacerbate COPD and asthma (Kaneko and Szallasi, 2014), whereas TRPV4 and TRPC6 are associated with lung edema (Weber et al., 2020; Weissmann et al., 2012).

TRPC1, TRPC3, TRPC5 and TRPC6 are reportedly involved in kidney disorders (Chubanov et al., 2017), including diabetic nephropathy and kidney fibrosis (Saliba et al., 2015). Whereas TRPC5 and TRPC6 may play roles in acquired and inherited FSGS, TRPC5 has been proposed to be a target for acquired FSGS (Pablo and Greka, 2019; Zhou et al., 2017). Moreover, TRPV1, TRPV2, TRPV4, TRPM4, TRPM8 and TRPA1 are implicated in lower urinary tract disorders, such as urinary incontinence and bladder-associated pain (Kaneko and Szallasi, 2014; Voets et al., 2019).

TRPM2, TRPM4, TRPM5 and TRPA1 have been implicated in insulin release from pancreatic β-cells (Colsoul et al., 2013). Deletion of Trpm2 or Trpm5 causes impaired glucose tolerance in mice (Kaneko and Szallasi, 2014), whereas activation of TRPM4 and TRPM5 promotes glucagon-like peptide 1-induced insulin release (Shigeto et al., 2015). Moreover, both TRPV1 and TRPA1 may be indirectly involved in diabetes (Derbenev and Zsombok, 2016).

TRPML1 in parietal cells mediates gastric secretion (Sahoo et al., 2017), and ML-IV patients exhibit constitutive achlorhydria. TRPV1, TRPV4 and TRPA1 are implicated in irritable bowel syndrome, visceral hypersensitivity (VH) and inflammatory bowel disease (IBD). Whereas TRPM8 also plays a role in IBD and VH, TRPC6 and TRPA1 are associated with intestinal fibrosis (Alaimo and Rubert, 2019).

There is emerging evidence indicating a role of the bacterial endotoxin-sensitive TRP channels, such as TRPA1, TRPV4, TRPV1, TRPM3 and TRPM8, in gut–brain cross talk in several entero-neuronal pathologies (Boonen et al., 2018; Meseguer et al., 2014; Startek and Talavera, 2020; Ye et al., 2021). Moreover, knockout of Trpv1, Trpa1 or both in mice has been shown to influence the gut microbiome and its metabolic pathways (Nagpal et al., 2020).

Activation of TRPV3, TRPV4, TRPC6, TRPM8 and TRPA1, and inhibition of TRPV1, contribute to skin barrier formation and wound closure. TRPV1, TRPV3, TRPA1, TRPC1, TRPC4 and TRPM8 are involved in skin inflammation. Moreover, activation of TRPA1, TRPM1 and TRPM7 contributes to hair growth and pigmentation, whereas TRPV1 and TRPV3 are negative regulators of these processes (Caterina and Pang, 2016; Yang et al., 2017).

TRPs are also involved in pathophysiological functions in other systems. For example, TRPM6 and TRPM7 are critical for maintaining Mg²⁺ homeostasis, and TRPV5 and TRPV6 are important in maintaining Ca²⁺ homeostasis (Chubanov et al., 2018; Mittermeier et al., 2019; van Abel et al., 2005). A number of TRPs contribute to immunity and the inflammatory response (Spix et al., 2020). Moreover, several TRPs have been proposed as potential targets of anti-cancer therapy (Stewart, 2020; Yang and Kim, 2020).

TRP channels play important physiological and pathological roles in various systems, and have been proposed as therapeutic targets for cardiovascular, neurological, renal and metabolic diseases. Although Qutenza (a capsaicin patch) is currently the only FDA-approved drug that targets TRPs, there are multiple ongoing clinical trials assessing other TRP-targeting compounds. The recent breakthroughs in solving atomic-resolution structures of TRP channels in the agonist-bound state will undoubtedly accelerate drug development targeting TRPs for various diseases.

We apologize to researchers whose work is not cited owing to space limitations.