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IUPHAR Compendium of Voltage-Gated Ion Channels 2005 |
Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts (D.E.C.); Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California (D.J.); Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore Maryland (C.M.); and Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany (G.S.)
Introduction
Introduction Structural Features Functional Features Classification and Nomenclature The TRPC Channels The TRPV Channels The TRPM Channels The TRPA Channel The TRPP Proteins The TRPML Proteins Summary
The transient receptor potential (TRP1) ion channels are named after the role of the channels in Drosophila phototransduction. The mammalian genes are encoded by at least 28 channel subunit genes (Fig. 1) (Clapham, 2003
; Moran et al., 2004). Six protein families comprise the mammalian TRP superfamily: the classic TRPs (TRPCs), the vanilloid receptor TRPs (TRPVs), the melastatin or long TRPs (TRPMs), the mucolipins (TRPMLs), the polycystins (TRPPs), and ankyrin transmembrane protein 1 (ANKTM1, TRPA1). The TRP channel primary structures predict six transmembrane (TM) domains with a pore domain between the fifth (S5) and sixth (S6) segments and both C and N termini presumably located intracellularly (Vannier et al., 1998). With the exception of some polycystins, TRPs are generally assumed to have six TM domains. This architecture is a common theme for hundreds of ion channels present in life forms ranging from bacteria to mammals.
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Despite the topographic similarities between the TRPs and the voltage-gated potassium channels, the TRPs are actually only distantly related to these channels. TRPs are found in eukaryotes from yeast to mammals, often functionally associated with G protein-coupled and growth factor (tyrosine kinase) receptors and phospholipase C (PLC) (Clapham, 2003). Other features include a 25-amino acid (aa) motif in some subfamilies (the TRP domain) containing a TRP box (EWKFAR) just C-terminal to S6. The TRP domain and box, as well as slight variations of these motifs, are present in all TRPC and TRPM channel genes, but not in other TRP channels. The N-terminal cytoplasmic domains of TRPC, TRPV, and TRPA channels contain ankyrin repeats, whereas those of the TRPC and TRPM channels contain proline-rich sequences in the region just C-terminal portion of the TRP domain, referred to as TRP box 2 (Montell, 2005). At present, no features, other than overall 6TM architecture/homology and cationic permeability, define the TRP family. Thus the definition of TRP channels will evolve as functions and structures are clarified.
Genes for the TRP ion channel subunits were first defined in the Drosophila visual system. In the trp mutant, the light response (receptor potential) decays during prolonged exposure to light. TRP-deficient flies are blinded by intense light because sustained Ca2+ entry via TRP ion channels and subsequent Ca2+-dependent adaptation is disrupted. Three genes (TRP, TRPL, and TRP
) encode TRP channels that are involved in fly vision, but there are at least 13 TRP-like genes in Drosophila. Genetic approaches in flies have not resolved the mechanism of TRP activation, but confirm the importance of PLC
and other components of the phosphatidylinositol pathway (Hardie et al., 2001; Minke and Cook, 2002; Hardie, 2003; Montell, 2003).
Six TM channels have two "domains," one (S1-S4) containing the S4 voltage sensor and a second (S5-S6) containing the 2TM pore and gate. A high-resolution structure of a TRP channel has not yet been solved. However, the 2TM structure of a bacterial K+ channel (KcsA) is analogous to the S5 and S6 domains joined by a short pore 
helix of the 6TM architecture (Doyle et al., 1996). The KcsA channel is a tetramer of 2TM helices. The helices corresponding to S5 face the lipid membrane whereas the helices corresponding to S6 line the pore. At both inner and outer membrane faces, layers of aromatic amino acids form a cuff around the pore. In KcsA, the selectivity filter is a narrow region near the outer face of the membrane lined by the carbonyl backbone of five conserved amino acids. These amino acids are not present as a group in the largely nonselective TRP channels. Presumably as in KcsA, the S6 segment lines the rest of the channel on its way to the cytoplasm. The S6 segment and the C-terminal amino acids extending into the cytoplasm are the most conserved between the TRP subfamilies and where the gating features of TRP channels are likely to emerge.
One 6TM channel subunit structure for the bacterial KV channel, Aeropyrum pernix, has been determined (Jiang et al., 2003). Flexibility around the S4-S5 linker required that Fab fragments be used to stabilize the protein to form a crystal. The structure was obviously deformed by the Fab fragments, flattening the S1-S4 segment and somewhat disordering the S1 and the N termini. The structure showed that the S3 helix split, with its distal portion (S3b) forming a hairpin loop with S4. For this voltage-gated channel, MacKinnon proposed that the S3b-S4 "paddle" moves from the inner to the outer membrane upon depolarization and pulls on the S5 helix to open the gate. Although the paddle model is currently debated, the general structure of 6TM TRPs is expected to resemble that of A. pernix and related structures that emerge.
Channels are opened or closed (gated) by conformational changes in the channel protein. K+ channels have two gates (upper and lower). Both gates must be open to conduct ions through the pore. Cells normally impart a high voltage (and thus energy) across the protein at rest (e.g., -70 mV) to hold it in its closed state. When this voltage is removed (depolarization), the protein relaxes into an open configuration (its low-energy state). The change in energy needed for gating can also be imparted by changes in temperature, chemical binding, or alteration of the channel protein [see Discussion in Clapham (2003)]. In practical usage, voltage-gating refers to channel opening that results from movement of the charged S4 segment in KV/NaV/CaV channels upon a change in transmembrane voltage. TRP channels lack these charged residues in S4, but their gating is affected by voltage changes. For TRPV1, M4, M5, and M8, the TRP channels that are most sensitive to voltage changes, an important question is which residues in the polypeptide chain convey voltage dependence. In general, TRP channel gating is not dominated by voltage but rather is effected by the energy differences accompanying changes in temperature, binding, and voltage. Perhaps a good analogy for TRP channels is the cyclic nucleotide-gated channels that are internal ligand-gated and are only weakly voltage-dependent.
Of the functionally expressed proteins, only TRPV5 and TRPV6 are Ca2+-selective (PCa/PNa >100). TRPM4b and TRPM5 are monovalent-selective (PCa/PNa <0.05), whereas all other TRP channels are relatively nonselective. The TRP channels do not have the sharp voltage sensitivity of the characterized channels in the CaV and NaV families. Thus, upon opening, they depolarize cells from their resting membrane potentials (approximately -70mV in most mammalian cells) to around 0 mV. In short, they depolarize cells and raise intracellular Na+ and usually Ca2+.
Two common signal transduction pathways that regulate the release of intracellular Ca2+ are the G protein-coupled and the tyrosine kinase activation of PLC. PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to form inositol 1,4,5-trisphosphate (IP3) that opens the IP3 receptor and liberates Ca2+ from the endoplasmic reticulum (Clapham, 1995). Accompanying these chains of events and not necessarily linked to Ca2+ store (endoplasmic reticulum) depletion is activation of the TRP channels. The details of these mechanisms are incompletely understood at present. The strongest associations between the phosphatidylinositol pathway and TRP channels involve PLC and PIP2. In Drosophila TRP channels, elements of these signal transduction pathways are linked by the scaffolding protein, INAD (Montell, 2003). In mammalian cells, this scaffolding function may be carried out by PLC (Patterson et al., 2002), Homer (Yuan et al., 2003), or other proteins.
Emptied Ca2+ stores (endoplasmic reticulum) some-how gate entry of external Ca2+ to replenish the deficit (Putney, 1977). The physiological hallmark of the store-operated Ca2+ entry process is a large receptor-mediated transient [Ca2+]i increase followed by a prolonged high [Ca2+]i plateau phase, dependent on [Ca2+]o. From their first identification in mammalian cells, TRPs were major suspects for the proteins comprising store-operated channels. However, most TRP channels that have been studied in detail are not gated by the usual manipulations defined as activating store-operated Ca2+ entry. Thus it is not accurate to refer to TRP channels as store-operated channels, although it may turn out that one or more of these channels participate in this process.
Classification and Nomenclature
In this article, the focus is on the TRP channels encoded by mammalian genes and the nomenclature system adopted by a number of workers in the field (Montell et al., 2002; Clapham, 2003).
The TRPC family can be divided into three subgroups by sequence homology as well as functional similarities: C1/C4/C5, C3/C6/C7, and C2. TRPC1 was the first member of the mammalian TRP family purported to form an ion channel (Zitt et al., 1996). Given the widespread expression of TRPC1 and its ability to coassemble with other TRPC subunits (Xu et al., 1997; Lintschinger et al., 2000; Strübing et al., 2001), TRPC1 might be a component of different heteromeric TRP complexes. The subgroup most closely related to TRPC1 comprises TRPC4 and TRPC5. TRPC4 and TRPC5 are PDZ motif-containing proteins that can form homomeric cation channels that are activated following stimulation of Gq-coupled receptors (Okada et al., 1999; Schaefer et al., 2000) as well as receptor tyrosine kinases (Schaefer et al., 2000). Coexpression of TRPC1 and TRPC4 or TRPC5 results in a nonselective cation channel with negative slope region depolarized to 0 mV. The details of the activation mechanism remain elusive, but the two primary products of PLC enzyme activity, IP3 and diacylglycerol (DAG), do not activate TRPC4 and TRPC5 (Hofmann et al., 1999; Schaefer et al., 2000). Both TRPC4 and TRPC5 contain a C-terminal PDZ-binding motif (VTTRL). PDZ domain scaffolding proteins, such as the Na+/H+ exchanger regulatory factor (NHERF) as well as signaling molecules such as PLC1, coimmunoprecipitate with TRPC4 and TRPC5 (Tang et al., 2000), indicating that the channels may be part of multimolecular signaling complexes similar to that in Drosophila photoreceptors. Growth factor stimulation initiates the rapid translocation of the transient receptor potential ion channel, TRPC5, from vesicles held in reserve just under the plasma membrane. This process, requiring PI3K, Rac1, and PI(4)K5, affects neurite extension rates in cultured hippocampal neurons and may be a general mechanism for initiating Ca2+ influx and cell morphological changes in response to stimuli (Greka et al., 2003; Bezzerides et al., 2004).
Less information is available about TRPC2, which shares approximately 30% sequence identity with the TRPC3/6/7 subfamily. Full-length TRPC2 mRNA and several N-terminal splice variants have been found in mouse and rat tissue, but TRPC2 seems to be a pseudogene in humans (Vannier et al., 1999; Liman, 2003). TRPC2 protein was localized to neuronal micovilli in rat vomeronasal organ (Liman, 2003) and in the head of mouse sperm (Jungnickel et al., 2001). TRPC2-deficient mice display abnormal mating behavior, consistent with a role for this channel in pheromone signaling (Stowers et al., 2002). Zufall and colleagues identified a DAG-gated TRPC2-dependent current in vomeronasal organ sensory neurons, suggesting that TRPC2 underlies neuronal excitability in pheromone sensing (Lucas et al., 2003).
TRPC3, TRPC6, and TRPC7 are 
75% identical. When expressed they constitute nonselective cation currents that rectify in both the inward (- voltages) and outward (+ voltages) directions. TRPC3, TRPC6, and TRPC7 are inwardly and outwardly rectifying, have relatively low selectivity for Ca2+ over Na+, and are activated by DAG (Hofmann et al., 1999; Okada et al., 1999; Putney et al., 2004). These channels seem to play important roles in vascular and airway smooth muscle (Corteling et al., 2004; Trebak et al., 2003; Yu et al., 2003). N-linked glycosylation (Dietrich et al., 2003), as well as Ca2+ modulation, may determine basal channel activity. Receptor-stimulated exocytosis may stimulate plasma membrane insertion of TRPC3 and C6 channels to contribute to receptor stimulation of Ca2+ influx (Cayouette et al., 2004; Singh et al., 2004). TRPC3 can assemble with TRPC1/4/5 in the embryonic brain (Strübing et al., 2003). TRPC3 channels can be directly phosphorylated by protein kinase G (Kwan et al., 2004) and TRPC6 by tyrosine phosphorylation by Src family protein tyrosine kinases (Hisatsune et al., 2004). In the mammalian brain, TRPC3 is activated through a pathway that is initiated by binding of brain-derived nerve factor to TrkB and engagement of a PLC and the IP3 receptor (Li et al., 1999). TRPC6 and 7 channels are regulated by Ca2+ through differential Ca2+/calmodulin-dependent and -independent mechanisms (Shi et al., 2004).
The TRPV channel subfamily has six members divided into two groups: V1/V2/V3/V4 and V5/V6. The vanilloid receptor, TRPV1, is the best understood ion channel in this class (Caterina et al., 1997; Caterina and Julius, 2001).
The expressed TRPV1 capsaicin receptor is a heat/proton/lipid/voltage-modulated Ca2+-permeant (PCa/PNa 10) ion channel (Caterina and Julius, 2001). A more voltage-gating-centric explanation is that at warmer temperatures (>37°C) or in the presence of capsaicin, TRPV1 current is activated by a more physiological range of voltages (Brauchi et al., 2004; Voets et al., 2004). TRPV1 is desensitized by internal Ca2+; it is not activated by store depletion. TRPV1, V2, and V3 are activated by the synthetic compound, 2-aminoethoxydiphenylborate (2-APB) (Chung et al., 2004b; Hu et al., 2004). Endogenous cannabinoid receptor ligands, such as anandamide, are potential TRPV1 agonists. The size of its current is increased by acid pH and is modulated by intracellular PIP2, which inhibits the channel (Chuang et al., 2001). Experiments using TRPV1 knockout mice confirm that it is essential for transducing the nociceptive, inflammatory, and hypothermic effects of vanilloid compounds and contributes to acute thermal nociception and thermal hyperalgesia following tissue injury (Caterina et al., 2000; Davis et al., 2000). However, one group proposed that intact nociceptors in vivo lacking TRPV1 and TRPV2 have normal heat responses (Woodbury et al., 2004). TRPV1 current is potentiated by bradykinin and nerve growth factor via several possible mechanisms, including PLC-mediated protein kinase C (PKC) activation and/or PIP2 hydrolysis and phosphatidylinositol 3-kinase (Premkumar and Ahern, 2000; Chuang et al., 2001; Zhuang et al., 2004). In afferent nerve terminals and within the epithelial cells that line the bladder lumen, TRPV1 is essential for normal mechanically evoked purinergic signaling by the urothelium (Birder et al., 2002). TRPV1 also has proposed far-reaching functions ranging from satiety (Ahern, 2003) to hearing modulation (Zheng et al., 2003).
The vanilloid receptor-like channel, TRPV2, is 50% identical to TRPV1, but is insensitive to capsaicin (Caterina et al., 1999). Like TRPV1 it is more permeable to Ca2+ than to Na+ (PCa/PNa = 3:1). It has been proposed to mediate high-threshold noxious heat sensation, perhaps in the lightly myelinated A
nociceptors, but its presence in nonsensory tissue suggests other functions as well. TRPV2 is immunolocalized to hypothalamic paraventricular, suprachiasmatic, and supraoptic nuclei, preferentially in oxytocinergic and vasopressinergic neurons (Wainwright et al., 2004), and in myenteric plexus and nodose ganglion afferent neurons (Kashiba et al., 2004). TRPV2 in mouse vascular myocytes may function as a stretch sensor in vascular smooth muscle (Muraki et al., 2003) and be downstream of protein kinase A activation in mast cells (Stokes et al., 2004).
TRPV3 is expressed widely but most strikingly in skin. Increasing temperature from 22 to 40°C in mammalian cells transfected with hTRPV3 elevates intracellular calcium by activating a nonselective cationic conductance (PCa/PNa 10:1) (Peier et al., 2002b; Smith et al., 2002; Xu et al., 2002). As in sensory neurons, the current is steeply dependent on temperature, sensitizes with repeated heating, and displays a striking hysteresis on heating and cooling (Xu et al., 2002), but the extent of expression in sensory neurons is controversial. Based on these properties, TRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1 and may play a role in pain. Primary keratinocytes isolated from mouse skin exhibit heat-evoked TRPV3 currents to mild increases in temperature (Chung et al., 2004a).
TRPV4 is 40% identical to TRPV1 and TRPV2 (Liedtke et al., 2000; Strotmann et al., 2000). When expressed in mammalian cells it comprises a moderately selective cation channel (PCa/PNa = 6), which, like TRPV1, displays a gently outwardly rectifying I-V relation. In isotonic media, TRPV4 is active, but the current is further increased by reduction of extracellular osmolality (cell swelling), with 50% activation by 270 mOsmol/l (physiological = 290 mOsmol/l). Hypertonic media (cell shrinking) decreased current activation. Deletion of the ankyrin repeat domains blunted the response to low osmolar solutions (Liedtke et al., 2000). Store depletion did not activate the channel. Anandamide and its metabolite arachidonic acid activate TRPV4 indirectly via the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids (Watanabe et al., 2003). Experiments with TRPV4-/- mice have given somewhat conflicting results in serum osmolar regulation by the central nervous system (Liedtke et al., 2003; Mizuno et al., 2003). TRPV4 may function as an osmo-transducer in primary afferent nociceptive nerve fibers (Alessandri-Haber et al., 2003), in water-impermeant nephron segments (Tian et al., 2004), and in human airway smooth muscle cells (Jia et al., 2004). Primary keratinocytes isolated from mouse skin exhibit strong heat-evoked TRPV4 currents to mild increases in temperature (Chung et al., 2004a). Trpv4-/- mice have reduced sensitivity to pressure and acidic nociception (Suzuki et al., 2003) and reduced heat hyperalgesia (Tominaga and Caterina, 2004).
TRPV5 and TRPV6 comprise a separate subfamily of TRPVs with only 30% identity with TRPV1. The expressed channels strongly inwardly rectify and are the most Ca2+-selective (PCa/PNa >100) (Nilius et al., 2000; Vennekens et al., 2000; Yue et al., 2001) of all TRP channels. These properties are consistent with proposed mechanisms for Ca2+-selective channels in which negatively charged glutamic or aspartic acid residues provide a binding site for divalents within the pore. Intra- and extracellular [Ca2+] (Yue et al., 2001; Bödding and Flockerzi, 2004) and calmodulin (Lambers et al., 2004) regulate TRPV6 activity. The localization of TRPV5 and TRPV6 to the proximal small intestine and collecting duct of the kidney, along with mouse knockout data, suggests that this family is important in calcium uptake via epithelial cells (Hoenderop et al., 2005). TRPV5-/- mice have diminished renal Ca2+ reabsorption despite enhanced vitamin D levels, resulting in hypercalciuria (Hoenderop and Bindels, 2005). Like several other TRP channels, TRPV6 has been linked to cancer progression and TRPV6 has been used as a prognostic marker for prostate cancer (Fixemer et al., 2003).
The TRPM subfamily has eight members divided into four groups: M1 (melastatin)/M3, M7 (TRP-PLIK)/M6, M2/M8, and M4/M5. Down-regulation of the 1533aa TRPM1 protein in the primary cutaneous tumor is a prognostic marker for metastasis in patients with localized melanoma (Duncan et al., 1998; Hunter et al., 1998). TRPM1 may be regulated through direct interaction with a cytosolic isoform generated by alternative RNA splicing (Xu et al., 2001), but TRPM1 ion currents have not been measured. The Caenorhabditis elegans gon-2 gene, a homolog of TRPM1, is required for postembryonic mitotic cell division of gonadal precursor cells (West et al., 2001). MITF, an essential transcription factor for melanocyte development, is an important transcriptional regulator of TRPM1 (Miller et al., 2004).
TRPM2 is a 1503aa protein that is highly expressed in brain (Nagamine et al., 1998) and present in blood cells. The channel is nonselective and displays a linear I-V relation. A NUDT9 Nudix hydrolase family domain within the TRPM2 sequence suggests that the channel may be regulated by nucleoside diphosphates, and current is increased when HEK-293 cells expressing TRPM2 are perfused with adenosine diphosphoribose or NAD (Perraud et al., 2001; Sano et al., 2001). In addition, the C-terminal NUDT9 domain confers adenosine diphosphoribose hydrolase activity. The channel is regulated by signaling pathways responsive to H2O2 and tumor necrosis factor-, suggesting that its physiological role may be as a sensor of redox status in cells (Hara et al., 2002; Wehage et al., 2002; Perraud et al., 2003).
Identified first by sequencing projects, the function of TRPM3 is poorly understood. The hTRPM3 gene maps to human chromosome 9q-21.12 and encodes a 1555-amino acid protein. Expressed primarily in kidney and, at lesser levels, in brain, testis, and spinal cord, hTRPM3 is nonselective (PCa/PNa 1.6). Hypotonicity reportedly increases calcium entry in TRPM3-expressing HEK293 cells (Grimm et al., 2003; Lee et al., 2003). D-erythro-Sphingosine, a metabolite in synthesis of cellular sphingolipids, but not sphingosine-1-phosphate and ceramide, activates TRPM3 (Grimm et al., 2004).
TRPM4 and TRPM5 have similar characteristics. TRPM4b, a splice variant of TRPM4, and TRPM5 are Ca2+-activated, voltage-modulated, monovalent-selective cation channels with 25 pS single-channel conductances (Launay et al., 2002; Hofmann et al., 2003; Nilius et al., 2003). Sustained increased [Ca2+]i desensitizes TRPM5 channels, but PIP2 partially restores channel activity (Liu and Liman, 2003). TRPM4/TRPM5-dependent currents contribute to myogenic vasoconstriction of cerebral arteries (Earley et al., 2004), and TRPM5 is important in taste (sweet, bitter, and umami) transduction (Perez et al., 2002; Zhang et al., 2003b). TRPM4b-mediated depolarization modulates intracellular calcium oscillations in T lymphocytes, with downstream effects on cytokine production (Zhang et al., 2003a; Launay et al., 2004). Decavanadate modulates TRPM4, but not TRPM5, apparently via a C-terminal positively charged domain (homologous to a site on SERCA pumps), by inhibiting voltage-dependent closure of the channel (Nilius et al., 2004).
TRPM6 and TRPM7 comprise a unique subfamily of TRP proteins with both channel and kinase activities. TRPM7, which has 1863 amino acid residues, was identified in a yeast two-hybrid screen as a protein interacting with PLC1 (Runnels et al., 2001). It seems to be ubiquitously expressed. The structure of the C-terminal kinase domain has been determined (Yamaguchi et al., 2001), and annexin 1 is one potential substrate (Dorovkov and Ryazanov, 2004). Although the kinase domain for TRPM7 has little sequence similarity to conventional protein kinases, its structure resembles that of many eukaryotic protein kinases (e.g., cAMP-dependent protein kinase) with the notable exception of having its own zinc-finger domain. TRPM7 exhibits a steeply outwardly rectifying conductance when expressed in mammalian cells (PCa/PNa = 3:1), passing very little inward current. TRPM7 is inhibited by intracellular magnesium (0.3-1.0 mM range) (Nadler et al., 2001). Although the mechanism of activation of TRPM6/7 is unknown, receptor-mediated activation of PLC by hormones or growth factors inhibits channel activity by hydrolyzing and reducing local PIP2 concentrations (Runnels et al., 2002). TRPM7 has been proposed to underlie the majority of cell deaths during prolonged anoxia in brain (Aarts et al., 2003). TRPM6 is the longest member (2011aa) of the TRP channel family and may form heteromeric channels with TRPM7. TRPM6 mutations in humans result in hypomagnesemia with secondary hypocalcemia (Schlingmann et al., 2002; Walder et al., 2002). Coupled with their permeation by Mg2+ (Nadler et al., 2001), this has led to the proposal that TRPM6 and M7 play a major role in Mg2+ homeostasis (Wolf, 2004).
TRPM8 is a 1104aa protein that does not seem to contain associated enzymatic domains. TRPM8 is a nonselective, voltage-modulated conductance. At colder temperatures (8-28°C) or in the presence of menthol, TRPM8 current is activated at a more physiological range of voltages (Brauchi et al., 2004; Voets et al., 2004). This channel is expressed in small-diameter primary sensory neurons, where it presumably functions as a thermosensor (McKemy et al., 2002; Peier et al., 2002a). TRPM8 is also expressed in prostate epithelium (Tsavaler et al., 2001), where it is proposed to be an androgen responsive channel (Zhang and Barritt, 2004).
TRPA1 is the most distinct of the four central (TRPC, V, M, and A) subclasses, with no known related family members, and contains more than a dozen ankyrin repeats in its N terminus. It was originally proposed to sense painfully cold temperatures (Story et al., 2003), but a more conservative description is that it is sensitive to membrane/cytoskeletal perturbations by cold, plant compounds such as mustard oils (Bandell et al., 2004; Jordt et al., 2004), and perhaps stretch [as the hearing transduction channel (Corey et al., 2004)]. TRPA1 is expressed in sensory neurons of dorsal root and trigeminal ganglia and the ear and, based on transcripts, is fairly widely expressed. TRPA1 is also activated downstream of G protein-coupled receptors that stimulate PLC and may depolarize nociceptors in response to proalgesic agents such as bradykinin, histamine, serotonin, or ATP. TRPA1 is expressed in trigeminal and dorsal root ganglia and the ear.
Polycystic kidney disease (PKD) proteins, or polycystins PKD2 (TRPP1), PKD2L1 (TRPP2), and PKD2L2 (TRPP3) comprise the 6TM Ca2+-permeant channels (Delmas, 2004). The much larger polycystin-1 (PKD1), polycystin-REJ, and polycystin-1L1 proteins are 11TM proteins that contain a C-terminal 6TM TRP-like channel domain. Polycystin1 is not known to form a channel by itself, but such a possibility has been raised by one recent study (Babich et al., 2004). According to another report, it complexes with TRPP2 to form a Ca2+-permeable nonselective cation channel with a linear I-V relation (Hanaoka et al., 2000). Autosomal dominant polycystic kidney disease is caused by mutations in polycystin-1 or TRPP1, leading to alterations in polarization and function of cyst-lining epithelial cells. Polycystin-1-/- and Trpp1-/- mice die in utero with cardiac septal defects and cystic changes in nephrons and pancreatic ducts (Wu et al., 1998). The mouse ortholog of TRPP2 is deleted in krd mice, resulting in defects in kidney and retina (Nomura et al., 1998; Pennekamp et al., 2002). Motile monocilia generate nodal flow and nonmotile TRPP1-containing cilia sense nodal flow, initiating an asymmetric Ca2+ signal at the left nodal border (Nonaka et al., 2002). Polycystin-1 and TRPP1 both seem to be targeted to primary cilia cells of renal epithelia, where the channel complex is gated by fluid flow (Nauli et al., 2003).
The mucolipins (TRPML1, 2, and 3; MCOLN1, 2, and 3) are 6TM channels that are probably restricted to intracellular vesicles (Bach, 2004). Mutations in MCOLN1 (TRPML1) are associated with mucolipidosis type IV, a neurodegenerative lysosomal storage disorder (Sun et al., 2000; Bach, 2001; Slaugenhaupt, 2002). The defect seems to be in sorting or transport in the late endocytic pathway. Mutations in a C. elegans TRPML1 homolog, cup-5, cause excess lysosome formation and apoptosis in all cell types (Hersh et al., 2002; Treusch et al., 2004). TRPML3 is present in the cytoplasm of hair cells and the plasma membrane of sterocilia. TRPML3 is mutated in the varitint-waddler mouse, resulting in deafness and pigmentation defects (Di Palma et al., 2002).
The TRP channels are a family of ion channel proteins that permeate Na+ and Ca2+ and, in several cases, Mg2+. Most cells contain several to many TRP subunits, complicating the separation of monomeric and heteromeric channel characteristics. The multipotent phosphatidylinositol pathway is involved in most TRP channel regulation, but the details of this regulation are just beginning to be elucidated. At this time there is no unifying theme in their mechanism for activation.
Since TRPs are intimately linked with intracellular Ca2+ signaling, they are implicated in the control of cell cycle progression, cell migration, and programmed cell death. TRP channels also seem to be important in epithelial uptake of divalent ions. Genetic approaches combined with robust assays have most clearly established their roles in sensory functions. Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 summarize the molecular, physiological, and pharmacological properties of these ion channels in more detail.
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Address correspondence to: Dr. David E. Clapham, Howard Hughes Medical Institute, Children's Hospital, 1309 Enders Bldg., 320 Longwood Ave., Boston, MA 02115. E-mail: dclapham{at}enders.tch.harvard.edu
The authors serve as the Subcommittee for Transient Receptor Potential Channels of the Nomenclature Committee of the International Union for Pharmacology.
Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
1 Abbreviations: TRP, transient receptor potential; TRPC, classic TRP; TRPV, vanilloid receptor TRP; TRPM, melastatin or long TRP; TRPML, mucolipin TRP; TRPP, polycystin TRP; TRPA, ankyrin TRP; TM, transmembrane; PLC, phospholipase C; aa, amino acid; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKD, polycystic kidney disease; 2-APB, 2-aminoethoxydiphenylborate; PKC, protein kinase C; SKF96365, 1-(-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole. 
Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, and Tymianski M (2003) A key role forTRPM7 channels in anoxic neuronal death. Cell 115: 863-877.[CrossRef][Medline]
Ahern GP (2003) Activation of TRPV1 by the satiety factor oleoylethanolamide. J Biol Chem 278: 30427-30434.
Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, and Levine JD (2003) Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39: 497-511.[CrossRef][Medline]
Babich V, Zeng WZ, Yeh BI, Ibraghimov-Beskrovnaya O, Cai Y, Somlo S, and Huang CL (2004) The amino-terminal extracellular domain is required for polycystin-1-dependent channel activity. J Biol Chem 279: 25582-25589.
Bach G (2001) Mucolipidosis type IV. Mol Genet Metab 73: 197-203.[CrossRef][Medline]
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