The transient receptor potential family of ion channels

  • Bernd Nilius1 and

    Affiliated with

    • Grzegorz Owsianik1Email author

      Affiliated with

      Genome Biology201112:218

      DOI: 10.1186/gb-2011-12-3-218

      Published: 17 March 2011

      Summary

      The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. Members of this family are conserved in yeast, invertebrates and vertebrates. The TRP family is subdivided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the latter is found only in invertebrates and fish. TRP ion channels are widely expressed in many different tissues and cell types, where they are involved in diverse physiological processes, such as sensation of different stimuli or ion homeostasis. Most TRPs are non-selective cation channels, only few are highly Ca2+ selective, some are even permeable for highly hydrated Mg2+ ions. This channel family shows a variety of gating mechanisms, with modes of activation ranging from ligand binding, voltage and changes in temperature to covalent modifications of nucleophilic residues. Activated TRP channels cause depolarization of the cellular membrane, which in turn activates voltage-dependent ion channels, resulting in a change of intracellular Ca2+ concentration; they serve as gatekeeper for transcellular transport of several cations (such as Ca2+ and Mg2+), and are required for the function of intracellular organelles (such as endosomes and lysosomes). Because of their function as intracellular Ca2+ release channels, they have an important regulatory role in cellular organelles. Mutations in several TRP genes have been implicated in diverse pathological states, including neurodegenerative disorders, skeletal dysplasia, kidney disorders and pain, and ongoing research may help find new therapies for treatments of related diseases.

      Gene organization and evolutionary history

      Transient receptor potential (TRP) genes were first described in the fruit fly Drosophila melanogaster. Studies in its visual system identified a visually impaired mutant fly that had a transient response to steady light instead of the sustained electro-retinogram recorded in the wild type [1]. This mutant was therefore called transient receptor potential; however, it took about two decades before the trp gene was identified by Montell and Rubin in 1989 [2]. From its structural resemblance to other cation channels and detailed analysis of the permeation properties of the light-induced current in the trp mutant, the product of the trp gene was proposed to be a six-transmembrane-segment protein that functions as a Ca2+-permeable cation channel [3]. Currently, more than 100 TRP genes have been identified in various animals (Table 1). Human TRP genes are diverse in length and range between 11.4 and about 911 kb, with the number of exons varying from 11 to 39. The overall protein sequence homology between subfamily members in the same species is usually about 35%, but for clear duplication pairs (such as TRPC6 and TRPC7, TRPM4 and TRPM5, and TRPV5 and TRPV6) this may reach 50 to 80%. Regulatory elements in promoters of TRP genes have not been identified.
      Table 1

      The TRP channel familya

       

      Drosophila melanogaster

      Caenorhabditis elegans b

      Ciona intestinalis b

      Fugu rubripes

      Danio rerio b

      Mus musculus

      Homo sapiens

      TRPC

      3

      3

      8

      8

      8

      7

      6

      TRPV

      3

      5

      2

      4

      4

      6

      6

      TRPM

      1

      4

      2

      6

      6

      8

      8

      TRPA

      4

      2

      4

      1

      2

      1

      1

      TRPN

      1

      1

      1

      -

      1

      -

      -

      TRPML

      4

      1

      9

      2

      2

      3

      3

      TRPP

      1

      1

      1

      4

      4

      3

      3

      Total

      17

      17

      27

      25

      27

      28

      27

      aTRP channels in the fruit fly Drosophila melanogaster, the worm Caenorhabditis elegans, the sea squirt Ciona intestinalis, the puffer fish (Seifuku, Fugu rubripes), the zebrafish (Danio rerio), mouse and human. The numbers correspond to proteins with distinct channel properties within each subfamily [104106]. For more detailed information concerning properties of TRP channels, please refer to the IUPHAR database [103]. bOthers report about 60 TRPs in zebrafish, 30 in sea squirts and 24 in C. elegans.

      From protein homology, members of the TRP channel family can be seen to fall into seven subfamilies [4]. The number of channels within each subfamily varies across species (Figure 1 and Table 1). The transmembrane segments tend to share the greatest homology within a particular subfamily. The TRPC subfamily ('canonical') comprises closest homologs of Drosophila trp channels. TRPVs ('vanilloid') are named after a founding member vanilloid receptor 1 (now TRPV1). The TRPM subfamily groups homologs of melastatin-1 (now TRPM1). TRPMLs and TRPPs include mucolipins and polycystins, respectively. All members of the TRPA subfamily are nociceptive channels characterized by the presence of about 14 ankyrin repeats. The TRPN subfamily is named after the 'NO-mechano-potential C' (NOMP-C) channel of Caenorhabditis elegans. So far, the only TRPN family member to be identified in vertebrates is from zebrafish [5].
      http://static-content.springer.com/image/art%3A10.1186%2Fgb-2011-12-3-218/MediaObjects/13059_2011_2493_Fig1_HTML.jpg
      Figure 1

      A phylogenetic tree of human TRP channels. Sequence homology analyses show that all TRP channels fall into seven subfamilies that comprise proteins with distinct channel properties. Because TRPC2 is a pseudogene in human and TRPNs are not present in mammals, we used mouse TRPC2 (ENSMUSP00000102562) and fish TRPN1 (ENSDARP00000093955) to show relations between all subfamilies. Protein sequences were aligned using ClustalW2 at the EMBL-EBI server. Phylogenetic distances were calculated using PAM matrix and the unrooted tree was obtained using NJplot [102]. The TRP subfamilies are represented by different colors. The scale bar represents 0.2 substitutions. Ensembl protein IDs for human protein sequences used in the analysis are as follows: TRPM1, ENSP00000380897; TRPM2, ENSP00000381023; TRPM3, ENSP00000350140; TRPM4, ENSP00000252826; TRPM5, ENSP00000387965; TRPM6, ENSP00000354006; TRPM7, ENSP00000320239; TRPM8, ENSP00000323926; TRPV1, ENSP00000174621; TRPV2, ENSP00000342222; TRPV3, ENSP00000301365; TRPV4, ENSP00000261740; TRPV5, ENSP00000265310; TRPV6, ENSP00000352358; TRPC1, ENSP00000273482; TRPC3, ENSP00000368966; TRPC4, ENSP00000369003; TRPC5, ENSP00000262839; TRPC6, ENSP00000340913; TRPC7, ENSP00000426070; TRPML1, ENSP00000264079; TRPML2, ENSP00000359640; TRPML3, ENSP00000304843; TRPP2, ENSP00000237596; TRPP3, ENSP00000325296; TRPP5, ENSP00000290431; TRPA1, ENSP00000262209.

      Within the six kingdoms of life, bacteria, protozoa, chromista, plantae, fungi and animalia [6], TRP-related genes seem to be found only in fungi and animalia. Despite extensive genomic studies, no single TRP-encoding gene has been identified in land plants so far, but the genome of chlorophyte algae seems to contain several types of putative TRP-like genes [7]. In the green alga Ostreococcus tauri, at least one of the putative genes might encode a potential TRP channel involved in a Ca2+ signaling pathway. Therefore, land plants might have lost TRP channels after their divergence from the chlorophyte algae [7].

      In fungi, the TRP family is represented by a single member, TrpY1 (also known as Yvc1 for yeast vacuolar conductance 1), which encodes a vacuolar membrane protein that functions as a mechano-sensor of vacuolar osmotic pressure in yeast [811]. The yeast TRP channel is activated in a Ca2+-dependent manner through stretching of the vacuolar membrane [12, 13] as well as by indole and other aromatic compounds [8, 9]. The action of aromatic ligands requires the presence of aromatic residues in the sixth transmembrane segment that might be counterparts of those found in several TRP channels of multicellular organisms [8, 9]. Because TrpY1p shares only partial homology with other known TRPs, it might be considered as one of the ancient mechano- and chemosensors [14, 15].

      Choanoflagellates are unicellular and colonial organisms considered to be the common ancestor of animals. It has been hypothesized that these colony-forming flagellate eukaryotes developed a Ca2+ signaling system that comprises homologs of various types of animal plasma membrane Ca2+ channels, including the store-operated channel, ligand-operated channels, voltage-operated channels, second messenger-operated channels, and five out of six animal TRP channel families [16]. Thus, it is very likely that these choanoflagellate genes served as ancestors for the evolution of different TRP subfamilies in animals; further expansions within subfamilies may have mainly occurred by gene duplications (Figure 1). During evolution, most vertebrates lost the mechanosensitive TRPN channels but almost doubled the number of TRPs involved in calcium and magnesium homeostasis, thermo- and chemosensing and calcium signaling (TRPCs, TRPVs and TRPMs; Table 1).

      Characteristic structural features

      Owing to the shortage of accurate X-ray crystallography data describing the three-dimensional structure of an entire TRP channel, most information concerning TRP domain composition comes from in silico and structure/function relationship studies. It is thought that most TRPs function as homotetramers. The formation of heteromultimeric channels between members of the same subfamily or different subfamilies has been described in several cases (such as between the TRPCs), and this could potentially create a wide variety of channels; however, it is debatable whether or not these multimeric channels are formed [17]. A typical TRP protein contains six putative transmembrane segments (S1 to S6) with a pore-forming reentrant loop between S5 and S6 [18, 19] (Figure 2). Intracellular amino and carboxyl termini are variable in length and consist of a variety of domains [18]. From cryo-electron microscopy data on TRPC3, the large intracellular domain can be seen as a 'nested box' structure: a 'wire frame' outer shell acts as a sensor for activators and modulators, and a globular inner chamber might modulate ion flow [20]. Interestingly, in a few cases the carboxy-terminal tails contain entire enzyme activities. For example, a Nudix hydrolase domain of TRPM2 functions as an ADP-ribose pyrophosphatase [21]. In TRPM6 and TRPM7 an atypical α-kinase domain is involved in regulation of channel function [22, 23]. Another feature in the amino termini of many TRPs is the presence of ankyrin repeats, 33-residue motifs consisting of pairs of antiparallel α-helices connected by β-hairpin motifs. The number of repeats in the ankyrin repeat domain (ARD) can vary between different TRPs: 3 to 4 in TRPCs, 6 in TRPVs, 14 to 15 in TRPAs and about 29 in TRPNs. Functionally, ARD seems to be connected with tetramerization of the channel and interactions with ligands and protein partners [24]. Currently, the ARD of TRPV channels is the only domain out of the entire TRP superfamily for which high resolution crystallographic data have so far been obtained [25, 26].
      http://static-content.springer.com/image/art%3A10.1186%2Fgb-2011-12-3-218/MediaObjects/13059_2011_2493_Fig2_HTML.jpg
      Figure 2

      Predicted structural topology of TRP channels. (a) All channels contain six transmembrane segments (S1 to S6) with a putative pore region (P) between S5 and S6. Amino and carboxyl termini are variable in length and contain different sets of domains. (b) Distribution of domains in selected human TRP channels [103]. The number and composition of domains vary between different TRP channels and are only partially preserved within members of the same subfamily. aa, amino acids; CaM, calmodulin; EF hand, helix-loop-helix Ca2+ binding motif; PH, pleckstrin homology domain; ER, endoplasmic reticulum; NUDIX domain, nucleoside diphosphate linked moiety X-type motif.

      The presence of other domains and motifs that influence channel functions, such as coiled coils, calmodulin-binding sites, lipid-interaction domains, EF hands or phosphorylation sites, is highly variable and very often not preserved in all members within the same subfamily (for more details see [18]).

      Localization and function

      TRPs are expressed in almost every cell type in both excitable and non-excitable tissues (Table 2). TRP channels are present in all cellular membranes, with the exception of the nuclear envelope and mitochondria. Most TRP channels are localized in the plasma membrane, where they have an essential role in the influx and/or transcellular machinery that transports Ca2+, Mg2+ and trace metal ions, and they modulate the driving force for ion entry. These contributions are essential for several physiological processes, ranging from pure sensory functions (such as pheromone signaling, taste transduction, nociception and temperature sensation) and homeostatic functions (such as Ca2+ and Mg2+ reabsorption and osmoregulation) to many other motile functions, such as muscle contraction and vasomotor control.
      Table 2

      Expression and function of human and mouse TRP channels

      Channel subunit

      Chromosomal location

      Cellular expression

      Physiological functions

      TRPC subfamily

        

      TRPC1

      Human: 3q22-q24; mouse: 9 E4

      Ubiquitous

      Generation of the excitatory postsynaptic potential in brain; netrin-1 and brain-derived neurotrophic factor (BDNF)-mediated growth cone guidance; connections to sleep/wakefulness states, alertness and appetite; brain development (together with TRPC5); glutamate signaling in hippocampus; regulation of smooth muscle contraction pulmonary system; platelet function; skeletal muscle differentiation; mechano-sensation?

      TRPC2

      Human: 11p15.4-p15.3 (pseudogene); mouse: 7 F1

      Dendritic tips of the vomeronasal sensory neurons and spermatozoa (mouse)

      Pheromone detection that regulates sexual and social behaviors, such as gender recognition and male-male aggression (mouse)

      TRPC3

      Human: 4q25-q27; mouse: 3 B

      Central nervous system (CNS) and smooth and cardiac muscle cells

      BDNF-mediated growth cone guidance (TRPC1-independent); spine formation in brain; γ-aminobutyric acid signaling in striatum; astrocyte function; moto-control in cerebellum; cerebral vaso-motor control; erythropoietin function; functional coupling to orexin receptor

      TRPC4

      Human: 13q13.1-q13.2; mouse: 3 D

      Placenta, adrenal gland, CNS, endothelium, smooth muscle cells, kidney, intestinal cells of Cajal

      Endothelium-dependent vasorelaxation and regulation of transcellular permeation of the endothelial layer; cell-cell adhesion in endothelium through junctional proteins; hypoxia sensing together with TRPC1

      TRPC5

      Human: Xq23-q24; mouse: X F2

      Brain, especially in fetal brain and very weak expression in other tissues

      Brain development (together with TRPC1); neurite growth, growth cone guidance and morphology; anxiety, fear and reward processing in nucleus accumbens

      TRPC6

      Human: 11q21-q22; mouse: 9 A1

      Smooth muscle cells, lung, brain, placenta, kidney (podocyte foot processes), spleen, ovary and small intestine, neutrophils

      Vaso-motor regulation; α1 signaling in smooth muscle; smooth muscle proliferation; angiogenesis; endocannabinoid signaling in the brain; promotion of dendrite growth and synapse forming in the developing brain; glomerular filter integrity in the kidney; platelet function; redox sensor; mechano-sensor?

      TRPC7

      Human: 5q31.2; mouse: 13 B2

      Pituitary glands, kidney and CNS (human); heart and lung; weak in CNS and kidney (mouse)

      Controls respiratory rhythm activity in pre-Bötzinger complex in the brain

      TRPV subfamily

        

      TRPV1

      Human: 17p13.3; mouse: 11 B3

      Dorsal root and trigeminal ganglia; spinal and peripheral nerve terminals, brain, skin (cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands), pancreas, bladder (urothelium, smooth muscle, blood vessels and neurons)

      Thermo-sensation (heat); autonomic thermoregulation; nociception; pain management; synaptic plasticity in the brain (long-term depression); endocannabinoid signaling in the brain; food intake regulation; growth cone guidance in the brain; osmosensing in the brain by a particular TRPV1 variant; multiple functions in the gut

      TRPV2

      Human: 17p11.2; mouse: 11 B2

      Dorsal root ganglia and CNS neurons, gastro-intestinal tract, spleen, mast cells, smooth, cardiac and skeletal muscle cells

      Thermo-sensation (noxious heat); nociception; axon outgrowth in spinal motor neurons; critical for phagocytosis in macrophages

      TRPV3

      Human: 17p13.3; mouse: 11 B4

      Dorsal root and trigeminal ganglion neurons, brain, keratinocytes, hair follicles, tongue and testis

      Thermo-sensation (moderate heat); nociception; skin integrity, wound healing, hair growth and sebocyte function

      TRPV4

      Human: 12q24.1; mouse: 5 F

      CNS (large neurons), trigeminal ganglia, heart, liver, kidney, skin (keratinocytes), osteoblasts, blood vessels (endothelium), bladder (urothelium) and testis, cochlea (inner and outer hair cells, marginal cells of the cochlear stria vascularis), kidney (epithelial cells of tubules and glomeruli)

      Thermo-sensation (moderate heat); mechano-sensation; osmo-sensation; nociception; modulation of cell migration; endothelium vaso-motor control and possible shear stress sensor; mechano-receptor in urothelium (important for voiding control); osteogenesis and osteoclast function; important in human bone and neurodegenerative diseases; control adherens junctions in skin; cochlea

      TRPV5

      Human: 7q35; mouse: 6 B2

      High in kidney; lower in gastro-intestinal tract, pancreas, testis, prostate, placenta, brain and salivary gland

      Ca2+ (re)absorption channel in kidney and intestines

      TRPV6

      Human: 7q33-q34; mouse: 6 B2

      High in gastro-intestinal tract; lower in kidney, pancreas, testis, prostate, placenta, brain and salivary gland

      Ca2+ (re)absorption channel in intestines and kidney; key player in Ca2+/1,25-dihydroxyvitamin D3-induced keratinocyte development in the skin

      TRPM subfamily

        

      TRPM1

      Human: 15q13-q14; mouse: 7 C

      Skin melanocytes, retinal bipolar ganglia

      Light response in ON bipolar retinal ganglia cells; tumor repressor in melanoma cells

      TRPM2

      Human: 21q22.3; mouse: 10 C1

      Brain, bone marrow, peripheral blood cells (neutrophils), lung, spleen, eye, heart and liver

      Oxidative and nitrosative stress response; activation of granulocytes; pancreas insulin release; critical in apoptosis

      TRPM3

      Human: 9q21.13; mouse: 19 C1

      Primarily in kidney; lower in brain, sensory neurons, testis, ovary, pancreas and spinal cord

      Steroid hormone (pregnanolon) sensor; possible regulator in endocrine pancreas, glia cells and cerebellar Purkinje cells

      TRPM4

      Human: 19q13.32; mouse: 7 B4

      Heart, exo- and endocrine pancreas, mast cells, smooth muscle, macula densa, lung and placenta

      Mast cell degranulation (histamine release) and migration as a critical Ca-impermeable cation channel regulating Ca2+ entry; catecholamine release from chromaffin cells; vasopressin release from paraventricular and supraoptic hypothalamic nuclei

      TRPM5

      Human: 11p15.5; mouse: 7 F5

      Tongue (taste bud cells), lungs, testis, digestive system, brain, endocrine pancreas

      Taste (sweet, bitter, umami); positive regulator of glucose-induced insulin release; trigeminal nasal chemoreception

      TRPM6

      Human: 9q21.13; mouse: 19 B

      Kidney, colon and intestine

      Mg2+ homeostasis and reabsorption in kidney and intestine

      TRPM7

      Human: 15q21; mouse: 2 F2

      Ubiquitous

      Mg2+ homeostasis and reabsorption in kidney and intestine; cell cycle control; gastrulation; development of thymocytes (thymopoiesis); cell migration; shear stress sensor?; skeletogenesis?

      TRPM8

      Human: 2q37.1; mouse: 1 C5

      Sensory dorsal root and trigeminal ganglia neurons, nodose ganglion cells innervating the upper gut, vascular smooth muscle cells, liver, gastric fundus, bladder (urothelium) and different tissues of the male genital tract; high in tumors from prostate, breast, colon, lung and skin

      Thermo-sensation (cold); sperm motility, acrosome reaction

      TRPA1 subfamily

         

      TRPA1

      Human: 8q13; mouse: 1 A3

      Hair cells, sensory dorsal root and trigeminal ganglia neurons, fibroblasts

      Thermo-sensation (noxious cold); the most versatile chemo-sensor; mechano-sensation?; nociception; olfactory responses; cold-induced contraction in colon and bladder

      TRPML subfamily

         

      TRPML1

      Human: 19p13.3-13.2; mouse: 8 A1.1

      Ubiquitous; intracellular ion channel

      Essential for endocytosis and endosomal/lysosomal function; regulation of autophagy

      TRPML2

      Human: 1p22; mouse: 3 H3

      Ubiquitous; intracellular ion channel

      Endosomal/lysosomal function

      TRPML3

      Human: 1p22.3; mouse: 3 H3

      Hair cells (stria vascularis, stereocilia); intracellular ion channel

      Endosomal/lysosomal function; autophagy; hair cell maturation?

      TRPP subfamily

        

      TRPP2

      Human: 4q22; mouse: 5 E4

      Ubiquitous; mostly in ovary, fetal and adult kidney, testis, and small intestine in both motile and primary cilia

      Cardiac, skeletal and renal development; integrity of the vessel wall; negative regulator of endogenous mechano-sensitive channels; mechano-receptor and flow-sensor in endothelium; apoptosis

      TRPP3

      Human: 10q24-q25; mouse: 19 D1

      Adult heart, skeletal muscle, brain, spleen, testis, retina and liver

      Renal development; part of putative sour sensor

      TRPP5

      Human: 5q31; mouse: 18 B3

      Testis, brain and kidney

      Spermatogenesis?

      BDNF, brain-derived neurotrophic factor; CNS, central nervous system.

      The functions of TRP channels at specific locations are often modulated by their associations with accessory proteins (such as TRPV4 and PACSIN3, a protein kinase C and casein kinase II substrate in neurons that is involved in synaptic vesicular membrane trafficking and regulation of dynamin-mediated endocytotic processes) and by formation of signaling complexes with various signaling proteins (such as TRPM4 and phospholipase C (PLC) isoforms and phosphatidylinositol kinases/phosphatases) [27, 28]. Currently, the mechanisms of intracellular trafficking of TRP channels and their guidance to the plasma membrane or to intracellular locations are mostly unknown [29].

      TRPs and disease

      Several TRP genes are implicated in a wide range of diseases in humans [30, 31]. These fall under the umbrella of the 'channelopathies', which are defined as diseases caused by impaired channel functions, resulting from either mutations in the encoding gene or an acquired mechanism, such as autoimmunity.

      TRPC6

      Mutations in TRPC6 are linked to the human proteinuric kidney disease called focal and segmental glomerulosclerosis (FSGS). FSGS patients show defects in the permeability barrier function in glomeruli, resulting in proteinuria and progressive kidney failure [3234].

      TRPV4

      Mutations in TRPV4 are linked with inherited disorders of bone growth, including brachyolmias and skeletal dysplasias mainly characterized by short trunk, scoliosis and mild short stature [35].

      TRPV4 has also been implicated in neurodegenerative disorders, such as scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot-Marie-Tooth disease type 2C (CMT2C, known also as hereditary motor and sensory neuropathy type 2C) [3639]. SPSMA is described by progressive weakness of scapular and peroneal muscle tissue, bone abnormalities and laryngeal palsy (the paralysis often being accompanied by loss of sensation). CMT2C results in progressive weakness of distal limbs, vocal cords, diaphragm, and intercostal and laryngeal muscles; impaired hearing and vision; some bone abnormalities, such as scoliosis; and bladder urgency and incontinence [36, 37, 39].

      TRPM1

      Melastatin or TRPM1 has been identified as a putative tumor suppressor in melanoma cells [4042]. Mutations in TRPM1 are linked to autosomal-recessive congenital stationary night blindness (CSNB). CSNB is a heterogeneous group of retinal disorders characterized by nonprogressive impaired night vision and variable decreased visual acuity as a consequence of the loss of function of rod and cone ON bipolar cells in the retina [4347].

      TRPM4

      Mutations resulting in Asn7Lys substitution in the amino-terminal part of the TRPM4 channel cause autosomal-dominant progressive familial heart block type 1 (PFHB1), a cardiac bundle branch disorder that affects the electrical conduction of the heart and may progress to a complete heart block. Increased TRPM4 mutant channel density in the plasma membrane, resulting from impaired endocytosis, very likely depolarizes the conduction system and causes the heart block [48].

      TRPM6

      The TRPM6 locus is associated with hypomagnesemia with secondary hypocalcemia (HSH/HOMG), an autosomal recessive disorder characterized by low Mg2+ and Ca2+ levels in serum, resulting from impaired intestinal Mg2+ absorption and renal Mg2+ leak [49, 50]. TRPM6 has a crucial role in active transcellular Mg2+ uptake at the apical membrane of the brush-border epithelium in intestines. Magnesium overload is also prevented by TRPM6, which is tightly regulated by the intracellular Mg2+ concentration [51].

      TRPA1

      The nociceptive TRPA1 channel is implicated in the etiology of an autosomal dominant familial episodic pain syndrome (FEPS) that is manifested by episodes of upper body pain, triggered by fasting and physical stress. FEPS patients show an enhanced cutaneous flare response with secondary hyperalgesia to punctuate stimuli in the presence of TRPA1 agonists [52].

      TRPML1

      Mucolipidosis type IV (MLIV) is caused by mutations in TRPML1. MLIV, an autosomal-recessive neurodegenerative lysosomal storage disorder is linked with psychomotor retardation, ophthalmologic abnormalities, failure of corpus callosum development, blood iron deficiency and achlorhydria [53]. TRPML1 is a calcium and iron permeable intracellular channel in lysosomes and, therefore, possible pathological mechanisms might include block of the endocytotic pathway at the late endosome-lysosome level, a defect in autophagy of endocytosed materials and impaired iron transport [54, 55].

      TRPP2

      Polycystic kidney disease (PKD), the most common inherited form of kidney failure, is associated with a mutation in TRPP2 (known also as polycystin 2). PKD is characterized by the development of large epithelial-lined cysts that are filled with fluid and can occupy much of the mass of the abnormally enlarged kidneys, thereby compressing and destroying normal renal tissue and impairing kidney function [56].

      Mechanism

      The activity of TRP channels is regulated by a variety of mechanisms. In general, these processes require the whole complement of post-transcriptional modifications, including G-protein-coupled receptor-related mechanisms, (de)phosphorylation and ubiquitination. Some more general mechanisms of TRP channel gating and their relevance to sensory modulation are discussed below.

      Membrane voltage

      A significant number of TRP channels, mostly involved in sensory perception, have intrinsic voltage dependence [5760]. The voltage-dependent activation of TRPs is sensitive to other triggers, such as the presence of ligands or changes in temperature that can alter the midpoint of the activation by several hundreds of millivolts [59, 61]. Similar to voltage-gated potassium channels, the molecular counterparts involved in voltage sensing are probably positively charged lysine and arginine residues in transmembrane segment S4 and the S4-S5 linker [61]. For a recent review on voltage sensing and its relevance to the gating of TRP channels in response to thermal and chemical stimuli, see [62].

      Membrane phospholipids

      Several studies report a direct effect of membrane phospholipids in the regulation of TRP channel activity (for example, of TRPA1 and TRPV1) [6365]. In particular, many TRPs are highly sensitive to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), the most abundant acidic phospholipid in the plasma membrane. The plasma membrane level of PtdIns(4,5)P2 can change rapidly because of the action of different PLC isoforms and phosphatidylinositol kinases/phosphatases, resulting in modulation of TRP channel activity [6668]. Many membrane-associated enzymes are also sensitive to changes in membrane PtdIns(4,5)P2 levels and, therefore, directly or indirectly can affect TRP channel function. For example, the membrane protein Pirt, which is required for the stimulatory effect of PtdIns(4,5)P2 on TRPV1 activity, interacts with both phosphoinositides and TRPV1 [64]. Cell-specific variations in the level of such regulatory proteins might explain at least some of the discrepancies relating to the effects of PtdIns(4,5)P2 on the TRP channel activity [29].

      Another PtdIns(4,5)P2-related mechanism has been proposed for the cold- and menthol-sensitive TRPM8 and the Ca2+-activated taste-transducing TRPM5 channels. An increased intracellular Ca2+ concentration leads to activation of Ca2+-dependent PLC (such as PLCδ1), resulting in depletion of cellular PtdIns(4,5)P2 and a subsequent channel decay [69, 70]. This PtdIns(4,5)P2 depletion does not lead to complete channel inactivation, but rather shifts the voltage dependence of channel activity to more positive potentials and reduces the channel sensitivity (desensitization) to ligands such as menthol (TRPM8) or Ca2+ (TRPM5) [71]. Endolysosome-localized TRPML channels interact directly with phosphatidylinositol 3,5-bisphosphate, an endolysosome-specific phosphoinositide, resulting in highly specific and potent activation of these channels [72].

      Phosphorylation

      Activation of PLC not only results in breakdown of PtdIns(4,5)P2 but also in the activation of protein kinase C (PKC). PKC-dependent phosphorylation might be a direct activatory mechanism or might sensitize the channel for other stimuli (for example, it sensitizes TRPV1 to heat or capsaicin) [73, 74]. However, PKC might downregulate the channel function: activation of PKC initiates the dephosphorylation of TRPM8 and subsequent inactivation of this channel [75]. The identities of the kinases that mediate phosphorylation of TRPM8 and the phosphorylation site in TRPM8 are still unknown.

      An additional pathway for the regulation of TRP channel activity following receptor stimulation is through protein kinase A (PKA). Activation of PKA by prostaglandin E2 stimulation potentiates TRPV1 responses and counteracts channel desensitization [74]. The PKA-dependent modulation of TRPV1 requires anchoring of PKA to the channel through the A-kinase anchoring protein AKAP150 and phosphorylation of a single amino-terminal serine residue [74, 76]. In TRPM8, PKA activation leads to desensitization of the channel activity by an as yet unknown mechanism. Both PKA- and PKC-dependent pathways have opposite effects on modulation of the heat-activated TRPV1 and the cold-activated TRPM8 [77].

      Ligands

      Most TRP channel activities are modulated by a large number of exogenous and endogenous ligands. In particular, temperature-sensitive TRPs seem to be preferred targets for plant-derived chemicals. The classic example is heat-sensitive TRPV1, which is activated by structurally unrelated botanical compounds such as capsaicin (the pungent extract of hot peppers [78]), resiniferatoxin (an active compound from the cactus Euphorbia resinifera [79]), piperine (the pungent component in black pepper [80]) and camphor (the waxy substance with penetrating odor extracted from Cinnamomum camphora [81], which also activates TRPV3 [82]). Other examples include TRPM8, a cold receptor directly activated by menthol (derived from the mint plant Mentha piperita) and eucalyptol (derived from the tree Eucalyptus globulus), [83, 84], and TRPV4, which is activated by bisandrographolide (derived from the plant Andrographis paniculata [85]). Thus, inherent thermal sensation linked to application of certain chemical compounds (chemesthesis) is related to activation of a single channel that can respond to both thermal and chemical stimuli (such as 'hot' chili pepper or 'cool' mint).

      In addition to natural plant-derived compounds, TRP channels respond to a wide range of synthetic ligands, many of which are important pharmacological tools that can be used to modulate channel functions. Some can activate more than one TRP channel (for example, 2-aminoethyl diphenylborinate activates TRPV1, TRPV2 and TRPV3 [86, 87] and icilin activates TRPM8 and TRPA1 [83, 88]), whereas some are relatively highly selective for a particular TRP channel (such as olvanil for TRPV1 [89] and 4α-phorbol-12,13-didecanoate (4α-PDD), lumiphorbols, phorbol-hexonates and GSK 1016790A for TRPV4 [9092]).

      Several TRP channels are receptors for endogenous compounds. TRPCs respond to diacyl glycerol, a lipid product derived from PtdIns(4,5)P2 breakdown catalyzed by PLC after a G-protein- or tyrosine-kinase-coupled receptor-dependent activation [93]. Arachidonic-acid-related compounds are involved in gating TRPV1 (arachidonoyl ethanolamide, 12,15-(S)-hydroperoxyeicosatetraenoic acid and leukotriene B4 [94]) and TRPV4 (5',6'-epoxieicosatrienoic acid [95]), and sphingosine, a primary part of sphingolipids, activates TRPM3 [96]. However, the mechanisms of these gating behaviors of TRP channels are currently unknown.

      Frontiers

      The discovery of TRP channels has revolutionized our understanding of many sensory and general physiological processes. TRPs generally act in concert with other ion channels and proteins. Given that, in many cases, these mechanisms are evolutionarily conserved from invertebrates to humans, it is not surprising that inherited impairments of TRP channel functions lead to disease. In addition, changes in channel expression levels or channel sensitization or desensitization, resulting in exaggerated or diminished responses to various pathological stimuli, can also contribute to pathophysiology of TRP-related diseases. Various endogenous agents released during early disease stages can also influence TRP channel functions and lead to inflammation and the progression of the disease (for example, release of leukotriene B4 leads to TRPV1 activation). These findings highlight TRP channels as important pharmacological targets. Several TRPV1 antagonists function as analgesic agents for the treatment of chronic pathological pain [97]. The classic natural pungent TRPV1 agonist, capsaicin, has been reported as a possible relief agent for some patients with tonic neuropathic pain [98]. Several lines of evidence suggest that blocking TRPC6 function might be clinically beneficial for FSGS patients [99]. Preliminary results demonstrate that the commonly used immunosuppressive agent FK-506 can inhibit TRPC6 activity in vivo and might be a possible treatment for idiopathic FSGS [100]. Another example is a small molecule antagonist of TRPV4, HC-067047, which may provide promising means for the treatment of bladder dysfunction [101]. Therefore, further understanding of the (patho)physiological roles and activation mechanisms of these channels may provide novel insights into the etiology and possible treatments of many TRP-related diseases.

      Declarations

      Acknowledgements

      We thank all members of our laboratory for helpful comments and discussions. This work was supported by grants from Interuniversity Attraction Poles Programme (Belgian State - Belgian Science Policy, P6/28), the Research Foundation-Flanders (G.0172.03 and G.0565.07), the Research Council of the KU Leuven (GOA 2004/07) and the Flemish Government (Excellentiefinanciering, EF/95/010).

      Authors’ Affiliations

      (1)
      Department of Molecular Cell Biology, Laboratory of Ion Channel Research, Campus Gasthuisberg, KU Leuven

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