Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
REVIEWS
You have accessRestricted Access

The Transient Receptor Potential Superfamily of Ion Channels

Chou-Long Huang
JASN July 2004, 15 (7) 1690-1699; DOI: https://doi.org/10.1097/01.ASN.0000129115.69395.65
Chou-Long Huang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

ABSTRACT. The transient receptor potential (TRP) superfamily of proteins is cation-selective ion channels with six predicted transmembrane segments and intracellularly localized amino and carboxyl termini. Members of the TRP superfamily are identified on the basis of amino acid sequence and structural similarity and are classified into TRPC, TRPV, TRPM, TRPP, TRPN, and TRPML subfamilies. TRP channels are widespread and have diverse functions, ranging from thermal, tactile, taste, osmolar, and fluid flow sensing to transepithelial Ca2+ and Mg2+ transport. Mutations of TRP proteins produce many renal diseases, including Mg2+ wasting, hypocalcemia, and polycystic kidney diseases. This review focuses on recent advances in the understanding of their functions.

The first transient receptor potential (TRP) protein was discovered in studies that examined Drosophila phototransduction (1). The photoreceptor cells of Drosophila exhibit sustained receptor potentials in response to continuous light exposure. The ionic basis for the sustained receptor potentials is influx of Ca2+ from the extracellular space. Cosens and Manning (1) reported in 1969 that one group of mutant flies exhibits TRP upon continuous light exposure and named it trp, for transient receptor potential. The trp gene was cloned in 1989 (2) and subsequently shown to encode a Ca2+-permeable cation channel (3). Since then, many channels that bear sequence and structural similarities to the Drosophila TRP have been cloned from flies, worms, and mammals. Together, they form the TRP superfamily.

Ion channels (e.g., voltage-gated K+ channels) are typically identified by their modes of activation and/or ion selectivity. Each family or superfamily of ion channels of similar activation and selectivity consists of multiple members of channel proteins with amino acid sequence homology. Unlike most ion channel families, the TRP superfamily of ion channels are identified on the basis of homology only. The mode of activation and selectivity for TRP channels are disparate. Some TRP channels are activated by ligands, whereas others are regulated by physical stimuli (e.g., heat) or yet-unknown mechanisms. All TRP channels are cation selective, but the selectivity ratio for Ca2+ versus the monovalent cation Na+ (PCa/PNa) varies widely, ranging from >100:1, to 1 to 10:1, to <0.05:1. The lack of common identifying features has in part contributed to the confusing nomenclature of TRP channels in the literature.

A recent consensus report proposed a unified nomenclature for the TRP superfamily (4). It classified TRP channels into TRPC, TRPV, and TRPM subfamilies. More recent classification has expanded TRP superfamily to include three additional, more distantly related subfamilies, TRPP, TRPML, and TRPN (Figure 1). Structurally, all of these TRP channels have six predicted transmembrane (TM) segments and N-terminal and C-terminal cytoplasmic tails similar to topologies of voltage-gated K+, Na+, and Ca2+ channels; cyclic nucleotide-gated channels; and hyperpolarization-activated channels (Figure 2). The fourth TM segment of TRP channels lacks the complete set of positively charged residues necessary for voltage sensing in many voltage-gated channels. The six TM polypeptide subunits of TRP channels likely assemble as tetramers to form cation-permeable pores. Across the entire superfamily, the amino acid sequence identity is only ∼20%. The similarity between subfamilies is limited primarily to the transmembrane segments. Within each TRP subfamily, amino acid sequence similarity is much higher and extends along the entire polypeptide. The N-terminal cytoplasmic region of some subfamilies contains several ankyrin-binding repeats (Figure 2). Ankyrin-binding repeats are 33-residue motifs that mediate cytoskeletal anchoring or protein–protein interaction. Some subfamilies contain a conserved stretch of 25 amino acids, called the TRP domain, or a kinase or phosphatase domain in the C-terminal cytoplasmic region.

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Classification of the transient receptor potential (TRP) superfamily.

Figure2
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 2. Domain organization of TRP channels. The TRP domain is a highly conserved 25—amino acid region. The region identified as “TRP box” is nearly invariant. X denotes any amino acid.

Molecular Identification and Characterization of TRP Channels

The TRPC Subfamily

The TRPC (for canonical TRP) subfamily is composed of proteins that are most highly related to Drosophila TRP. It consists of seven mammalian members, TRPC1 to 7 (5–10⇓⇓⇓⇓⇓). Members of the TRPC subfamily contain three to four ankyrin repeats in the N-terminus and a conserved TRP domain in the C-terminus (Figure 2). Human TRPC subfamily can be divided into three subgroups on the basis of amino acid homology: TRPC1, TRPC4/5, and TRPC3/6/7. TRPC2 is a pseudogene in human but seems to encode an expressed protein in rat and mouse (8–10⇓⇓). TRPC4 and TRPC5 share ∼65% homology. TRPC3, TRPC6, and TRPC7 share ∼70 to 80% homology. Members of the TRPC subfamily are highly expressed in central nervous system and to lesser degrees in many peripheral tissues, including kidney. The selectivity ratio for Ca2+ versus Na+ (PCa/PNa) for TRPC channels ranges from 0.5 to 10:1. TRPC channels are involved in Ca2+ entry in response to activation of phospholipase C (PLC) by membrane receptors and thus play important roles in the regulation of intracellular Ca2+ concentration by hormones and growth factors (see Functions of TRP Channels).

The TRPV Subfamily

The TRPV subfamily is named after the first mammalian member of the subfamily, vanilloid receptor 1 (VR1). It contains six mammalian members, TRPV1 to 6. TRPV1 (VR1) was isolated by expression cloning using capsaicin, a vanilloid compound derived from “hot” pepper, as a binding ligand (11). TRPV2 to 4 were isolated by searching for expressed sequence tags (EST) with amino acid homology to TRPV1 (12–16⇓⇓⇓⇓). TRPV1 to 4 share 40 to 50% amino acid homology, are Ca2+-permeable nonselective cation channels (PCa/PNa ∼3 to 10:1), and have steep temperature sensitivity. TRPV5 and TRPV6 were isolated by expression cloning of proteins that mediate Ca2+ transport in kidney and intestine, respectively (17,18⇓). They are the most highly Ca2+-selective TRP channels (PCa/PNa >100:1). Overall, TRPV subfamily channels contain three to four ankyrin repeats in the N-terminus and a TRP domain in the C-terminus (Figure 2). TRPV channels are also present in invertebrates. Invertebrate TRPV proteins include C. elegans OSM-9 and OCR (for OSM-9/capsaicin receptor related) (19,20⇓). OSM-9 is more closely related to TRPV5/6 than TRPV1 to 4 at the amino acid level.

The TRPM Subfamily

The TRPM subfamily is named after the founding member, melastatin. Melastatin, TRPM1, is a tumor suppressor protein isolated in a screen for genes whose level of expression (inversely) correlated with the severity of metastatic potential of a melanoma cell line (21). There are eight mammalian members in the TRPM subfamily. TRPM subfamily channels lack ankyrin repeats in the N-terminus but contain the TRP domain in the C-terminus (Figure 2). The C-terminus of TRPM proteins is considerably longer than the corresponding region of other TRP. The C-terminus of several members of TRPM contains enzyme domains. These TRPM proteins are thus called “chanzymes.”

TRPM2 (initially called TRPC7 and LTRPC2) is a Ca2+-permeable channel that contains a C-terminal ADP-ribose pyrophosphatase domain (22–25⇓⇓⇓). ADP-ribose pyrophosphatase catalyzes the hydrolysis of nucleoside diphosphate derivatives. The domain in TRPM2, however, is an ineffective hydrolase but binds ADP-ribose and NAD (23–25⇓⇓). ADP-ribose and NAD directly activate TRPM2 to allow Ca2+ influx. ATP counteracts the NAD-induced activation. TRPM2 is also regulated by H2O2 and TNF-α (26,27⇓). Thus, TRPM2 may be important in sensing oxidative stress and in linking apoptosis with the metabolism of ADP-ribose and NAD.

TRPM3 is a Ca2+-permeable, nonselective cation channel whose activity is increased by hypotonicity (28). TRPM4 and TRPM5 are the only TRP channels that are permeable to monovalent cations but not Ca2+ (PCa/PNa <0.05:1) (29,30⇓). However, they are activated by intracellular Ca2+ (29,30⇓). Activation of TRPM4 and TRPM5 by intracellular Ca2+ leads to membrane depolarization. TRPM6 and TRPM7 both contain a C-terminal protein kinase domain (31–36⇓⇓⇓⇓⇓). The role of these kinase domains in the channel function of TRPM6 and TRPM7 is not known. TRPM8 is an outward rectifying channel that can be activated by cold (37,38⇓). It was isolated by expression cloning of a menthol receptor from sensory neurons.

The TRPP Subfamily

The TRPP subfamily is so named because of its founding member, PKD2. PKD2 (also called TRPP2) was discovered as one of the gene products mutated in autosomal dominant polycystic kidney disease (39). PKD2 is a six-TM protein that shares ∼25% amino acid identity with the closely related TRPC3 and TRPC6 over the region spanning TM segments IV through VI (40). Mammalian PKD2 is a Ca2+-permeable, nonselective cation channel (41). It contains a Ca2+-binding EF-hand motif and a coiled-coil domain in the C-terminus but does not include any ankyrin repeats or a TRP domain. PKD2L1 (TRPP3) and PKD2L2 (TRPP5) are homologues of PKD2 (42,43⇓). No mutations in either PKD2L1 or PKD2L2 have been found in patients with autosomal dominant polycystic kidney disease.

The much longer PKD1 protein (TRPP1) is an 11-TM protein (44). The last six TM segments of PKD1 are homologous to PKD2 and other related TRP channels (45). PKD1 is not known to form a channel by itself but may complex with PKD2 to regulate its channel activity (46).

The TRPN Subfamily

The first member of the TRPN subfamily is Drosophila NOMPC protein. NOMPC is the gene product of mutant flies with the phenotype of “no mechanoreceptor potentials” (47,48⇓). The Drosophila NOMPC protein shares significant homology with the TRP superfamily. The N-terminus of NOMPC contains 29 ankyrin repeats (Figure 2). A NOMPC orthologue was also identified in C. elegans (48) and in zebrafish (49). No TRPN have been found in mammals.

The TRPML Subfamily

The TRPML subfamily is defined by a human protein, mucolipin 1. Mucolipin 1 (TRPML1) is a 580–amino acid long protein probably restricted to intracellular vesicles (50–52⇓⇓). TRPML1 contains two proline-rich regions, a lipase serine active site in the N-terminus and a dileucine motif suggestive of lysosomal targeting in the C-terminus. Mutations in TRPML1 cause mucolipidosis type IV (MLIV), a rare autosomal recessive lysosomal storage disease that affects brain, eyes, and gastric function. The defect in MLIV seems to be in sorting or transport of intracellular vesicles. Channel function of TRPML1 has recently been reported (53). TRPML2 and 3 were also identified (54). TRPML3 is present in the cytoplasm of hair cells and the plasma membrane of stereocilia.

Functions of TRP Channels

The TRP superfamily comprises a large number of ion channels with diverse functions. The division into subfamilies on the basis of amino acid sequence and structural similarity does not provide functional classification for TRP proteins. For example, members of the TRPV subfamily are involved in thermal and nociceptive sensing as well as transporting Ca2+ in epithelial tissues. Moreover, thermal sensing is not restricted to members of the TRPV subfamily. TRPM8 also functions in thermal sensing. In this section, TRP channels are discussed on the basis of their functions.

Role of TRP in PLC-Dependent Ca2+ Influx

In virtually all eukaryotic cells, activation of PLC-coupled membrane receptors by hormones leads to an increase in intracellular Ca2+. Activation of PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). The increase in intracellular Ca2+ is initially produced by release of Ca2+ from intracellular IP3-sensitive stores and is followed by an influx of Ca2+ from the extracellular space through plasma membrane Ca2+-permeable channels. The entry of Ca2+ from the extracellular space is important for refilling intracellular stores. The mechanism for Ca2+ entry has been studied extensively. In one mechanism, termed “store-operated Ca2+ entry,” the emptying of intracellular stores activates surface membrane Ca2+ channels via either diffusible factors or a direct interaction between IP3 receptors and surface Ca2+ channels (55–57⇓⇓). These Ca2+-permeable channels on the cell surface are called store-operated channels (SOC). Not all Ca2+ entry after PLC activation is dependent on store depletion. Ca2+ entry may also be due to activation of surface Ca2+ channels by other intracellular second messengers, such as DAG.

Store-operated Ca2+ entry is widespread and represents the major mechanism of regulation of Ca2+ influx in nonexcitable cells such as renal tubule cells. Because of their prevalence and importance, considerable effort has been devoted to identifying SOC and to understanding the mechanism of activation. The discovery that Drosophila TRP proteins were PLC-dependent Ca2+ influx channels has fueled much of the interests and hopes for isolation of SOC. TRPC channels are the closest relatives of Drosophila TRP and all are activated by G protein–coupled receptors. A vast number of papers have reported that many TRPC channels function as SOC. Zhu et al. (7) first reported that expression of human TRPC3 in cultured human embryonic kidney (HEK) cells gives rise to agonist- and thapsigargin-activated channel activity. Because thapsigargin depletes intracellular Ca2+ stores by inhibiting the endoplasmic reticulum Ca2+-ATPase, the authors concluded that TRPC3 proteins constitute subunits of SOC. Others have also reported that reduction of TRPC1 expression using antisense oligonucleotides leads to inhibition of endogenous SOC (58). A dominant-negative form of TRPC3 inhibits store-operated Ca2+ entry in umbilical vein endothelial cells (59).

Kiselyov et al. (60) reported that in HEK cells that stably express human TRPC3, IP3 activates single channels in excised inside-out patches. This activation is lost upon extensive washing of excised patches and is restored by addition of IP3-bound IP3 receptor. Kiselyov et al. concluded that TRPC3 is a store-operated channel that is activated via direct interaction with IP3 receptors. Similar store-operated channel activity has been reported for TRPC4 and TRPC7 channels (61,62⇓). Recently, knockout mice that lack the TRPC4 gene have been created (61). TRPC4−/− mice exhibit impaired vasorelaxation of aortic rings; aortic endothelial cells isolated from knockout mice exhibit defective store-operated Ca2+ entry (61), providing support that TRPC4 channels function as SOC.

However, many publications also dispute the conclusion that TRPC proteins are SOC. For example, Zitt et al. (63) reported that TRPC3 expressed in Chinese hamster ovary (CHO) cells is not store dependent but rather is activated by DAG. Hofmann et al. (64) confirmed these findings and reported that TRPC3 and TRPC6 are activated by DAG. Drosophila TRP proteins, the earliest and most promising candidates for SOC, have now been shown definitively not to be store dependent. Mutant flies that lack the IP3 receptor gene remain capable of generating normal sustained receptor potentials on continuous light exposure (65). It is now believed that Drosophila TRP proteins are activated by DAG, polyunsaturated fatty acids (downstream metabolites of DAG), and/or a reduction of phosphatidylinositol 4,5-bisphosphate2 (66,67⇓). Thus, the question of whether and which TRP constitutes SOC remains unsettled. The reason(s) for the differences among these studies is not known. One possibility is that different expression systems were used in these studies. Because virtually every cell expresses some TRP proteins endogenously, expressed exogenous proteins may form heteromultimers with endogenous proteins and/or activate endogenous TRP proteins. Irrespective of the mechanism of activation (store dependent or store independent), it is clear that TRPC play an important role in PLC-dependent Ca2+ entry.

TRP as Thermal and Noxious Receptors

TRPV1 was first identified as a receptor that binds capsaicin. Capsaicin is an ingredient of chili peppers that produces the “hot,” spicy sensation. Capsaicin sensitivity is a functional hallmark of nociceptive sensory neurons. Consistent with this concept, TRPV1 is expressed in primary afferent sensory neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG) (68). Binding of capsaicin activates TRPV1. TRPV1 is also activated by noxious heat (≥43°C) and low pH (5.9) (68). Gating by heat is direct, whereas low pH reduces the temperature threshold for activation. In addition, inflammatory mediators activate TRPV1 (69,70⇓). Because tissue injury produces acidosis and inflammation, TRPV1 is a polymodal detector of injury.

TRPV2 is ∼50% identical to TRPV1 but is insensitive to capsaicin and low pH (12). Instead, it is activated by heat at a higher temperature threshold than TRPV1 (≥52°C). TRPV3 is temperature sensitive in the physiologic temperature range (31 to 39°C) (13–15⇓⇓). TRPV4 was first described as a channel that was activated by hypotonicity-induced cell swelling (16). TRPV4 is also temperature sensitive but at a low activation threshold (≥25°C) (71) and is capable of integrating a large number of stimuli (72) (see below). Both TRPV3 and TRPV4 are present in sensory neurons and in keratinocytes, where they might function as thermal sensors in the skin.

Further evidence that TRP proteins are essential thermal sensors comes from recent discovery that other TRP proteins function as receptors for cold. TRPM8, isolated by expression cloning of a menthol receptor, is activated by cold (8 to 28°C) (37,38⇓). Its activation by menthol produces the cooling sensation of the compound. TRPM8 is found in ∼10% of DRG or TG neurons. Cold temperatures below 28°C evoke large currents through TRPM8, which saturates near 8°C. Knowing that some neurons are activated only by noxious cold temperature (<17°C), Story et al. (73) searched for additional cold sensors and found a unique protein named ANKTM1. ANKTM1 is found in humans and mice and is distantly related to the invertebrate TRPN subfamily but has little sequence similarity to other mammalian TRP proteins (Table 1). It may be considered the founding member of a new subfamily, TRPA (not shown in the phylogenetic tree in Figure 1). ANKTM1 is expressed in a subset of sensory neurons that also express TRPV1.

View this table:
  • View inline
  • View popup

Table 1. Functions of mammalian TRP proteinsa

In summary, at least six TRP proteins are involved in temperature sensing. The unique threshold for activation but overlapping range of sensitivity for these proteins allows organisms to have a combinatorial mode of thermal coding that responds to temperatures that span between 8 and 60°C. Thus, noxious cold temperatures activate ANKTM1 and TRPM8, whereas cool temperatures activate TRPM8 alone. Warm temperatures activate TRPV3 and TRPV4, whereas moderate noxious heat activates TRPV1 and high noxious heat activates TRPV1 and TRPV2.

TRP as Mechanosensors

Mechanosensation is the basis for hearing, osmolar sensing, stretch, touch, and flow sensing (74). Hearing is initiated by the bending of cilia on the inner ear hair cells in response to incoming sound waves. Bending of cilia activates “transduction channels” that convert the mechanical stimulus to electrical signals, which travel by the auditory nerve fibers to the brain. Vestibular hair cells in the semicircular canals contain similar types of transduction channels to sense movement of the head.

The best studied mechanosensitive channel is the bacterial MscL channel (75). The MscL channel is a mechanosensitive channel that is activated by lateral membrane tension. The existence of these channels in Archaebacteria highlights the ancient nature of mechanotransduction and its critical role in all cells. No MscL homologues have been identified in eukaryotes. Eukaryotic mechanosensitive channels include at least two unrelated gene families, the DEG/ENaC (degenerins/epithelial Na+ channels) superfamily (reviewed in ref. 74) and the TRP superfamily. The TRP superfamily of proteins contributes to all modalities of mechanosensation from flies, worms, and fish to humans. The first cloned TRP channel implicated in mechanosensation is the C. elegans OSM-9 of the TRPV subfamily. Worms with mutations in the osm-9 gene are defective in osmotic avoidance, sensitivity to nose touch, and attraction to volatile odorants (19). NOMPC, a member of TRPN, is located in mechanosensory bristles and is essential for response to touch stimuli in flies (47,48⇓). In zebrafish, NOMPC is present in sensory hair cells (49). Knockdown of NOMPC in zebrafish impairs the acoustic startle reflex.

OSM-9 and NOMPC are not present in mammals. Mammalian mechanosensitive TRP proteins include TRPV4, TRPP, and possibly TRPML3. As discussed above, TRPV4 is a mammalian TRPV member that senses temperature, osmolarity, and other mechanical stimuli (16,71,72⇓⇓). Besides sensory neurons, TRPV4 is expressed in renal distal tubules, where interstitial osmolarity fluctuates markedly. TRPV4 is expressed in osmosensing circumventricular organs of brain, mechanosensitive heart and vascular endothelial cells, and mechanosensitive inner ear hair cells (16,71,72⇓⇓). TRPV4, however, is not essential for all of these functions. TRPV4−/− mice exhibit impaired osmotic regulation and a reduced response to noxious mechanical stimuli but have no detectable defects in hearing and auditory responses and maintaining core body temperature (76). TRPV4 knockout mice have a slightly higher serum osmolarity during water restriction and a lower serum vasopressin level during hyperosmolar challenge. Urine osmolarity is not different between knockout mice and control littermates receiving dDAVP infusion, suggesting that defects in osmotic regulation reside in central osmosensation, not in the kidney tubules.

Varitint-waddler mice are spontaneously occurring mutant mice characterized by deafness and circular behavior indicative of vestibular dysfunction (54). Mutant mice show hair cell degeneration in the first few weeks after birth. Positional cloning has recently identified Mcoln3 (TRPML3) as the gene mutated in varitint-waddler mice (54). TRPML3 localizes to intracellular vesicles and plasma membrane of stereocilia in Cochlea hair cells. The physiologic role of TRPML3 in hair cells is unknown. However, its location in stereocilia raises an interesting possibility that it may function as a transduction channel in hair cells.

PKD1 and PKD2 are TRPP proteins that likely play important roles in sensing fluid flow in renal tubules. PKD1 and PKD2 proteins (also called polycystin-1 and -2) both are localized in the apical cilium of renal tubular epithelial cells (77,78⇓). Bending of the cilia in cultured epithelial cells by flow causes calcium influx (79). Nauli et al. (80) recently reported that the calcium response to bending is diminished in cells that lack cilia, in cells that lack PKD1, or in cells that are treated with a blocking antibody to PKD2. These experiments suggest that PKD1 and PKD2 are involved in calcium influx activated by flow-induced bending of the apical cilium. Defects in fluid flow sensation by cilia and Ca2+ influx likely play pivotal roles in cyst formation in kidney and other organs in polycystic kidney diseases.

PKD proteins are also important in embryonic development. The embryonic ventral node, which appears in the gastrulation stage of vertebrate development, consists of a dorsal layer of ectoderm over a ventral layer of cells each containing a single cilium. Normal left-right body asymmetry depends on a leftward nodal flow generated by ciliated nodal cells. McGrath et al. (81) showed that there are two types of nodal cilia: one is motile but does not contain PKD2, and the other is nonmotile but contains PKD2. The motile ciliated cells located in the center of the node generate fluid flow that is sensed by nonmotile PKD2-containing ciliated cells in the peripheral region of the node. Increase in cytosolic Ca2+ in the left side of the node is thought to be important for establishing left-right asymmetry. Homologues of PKD1 and PKD2 are also present in C. elegans (82,83⇓), where they are located in ciliated mechanosensory neurons of male copulatory organs and in other ciliated mechanoreceptors. Together, these reports support the important role of PKD proteins in ciliary mechanosensation.

The identity of pore-forming protein(s) in PKD2-related channel activity remains unclear. Channel activity recorded from PKD2 proteins reconstituted in lipid bilayer is strongly voltage dependent: Open probability is higher at hyperpolarized membrane potentials and reduced to near zero at positive membrane potentials (41,84⇓). This voltage dependence of single-channel open probability would predict a strongly inwardly rectifying whole-cell current if PKD2 proteins were expressed on the surface membrane and solely contributed to membrane currents. However, expression of PKD2 with or without PKD1 in cultured cells produces surface membrane whole-cell currents with nearly linear current–voltage relationships (85,86⇓). It has been shown that PKD2 protein can physically associate with TRPC1 (40). The molecular composition of pore-forming protein(s) underlying the whole-cell currents in PKD2-expressing cells versus the single-channel activity recorded in lipid bilayer deserves further investigation (87).

TRP as Taste Sensors

Salt and sour taste are detected by members of the DNG/ENaC superfamily. The ability of certain TRP proteins to integrate physical and chemical stimuli (e.g., TRPV4, OSM-9) suggests that TRP may play roles in the perception of taste. Indeed, it has been found that TRPM5 is expressed in taste buds. TRPM5 may be responsible for perception of bitter and/or sweet compounds (88).

Role of TRP in Divalent Ion Homeostasis

(Re)absorption of Ca2+ and Mg2+ ions in kidney and intestine is essential for homeostasis of these ions in the body. Transepithelial transport of Ca2+ and Mg2+ in these tissues occurs via paracellular as well as transcellular routes. Transcellular reabsorption of these ions, although accounting for a smaller portion of the total reabsorption than paracellular route, is the primary target for regulation by hormones and acid–base disturbances. Transcellular reabsorption of Ca2+ and Mg2+ is mediated by diffusion into cells through ion channels in the apical membrane followed by extrusion across basolateral membranes via pumps or exchangers. TRPV5 was initially identified as the apical Ca2+ entry channel in kidney and was localized to the Ca2+-reabsorptive distal convoluted tubules (DCT) (17). TRPV6 was identified as the apical channel responsible for intestinal absorption of Ca2+ (18). Recent studies, however, have found that both TRPV5 and TRPV6 are expressed in the DCT of kidney, where they may form heteromultimers (89). TRPV6 is also expressed in medullary collecting ducts (90), where Ca2+ reabsorption is not known to take place under physiologic conditions. The role of TRPV6 in this segment remains to be identified. Mice with targeted ablation of TRPV5 have been generated (91) and exhibit polyuria and hypercalciuria, providing support for an essential role of TRPV5 in renal Ca2+ reabsorption. Consistent with the phenotype of renal Ca2+ wasting, TRPV5 knockout animals exhibit compensatory intestinal hyperabsorption of Ca2+ and reduced bone thickness.

Increased acid load in conditions such as high dietary protein intake and metabolic acidosis increases urinary Ca2+ excretion (92). A recent study reported that extracellular protons bind to a titratable amino acid, glutamate-522 (a “pH sensor”), in the extracellular loop of rabbit TRPV5 and inhibit its activity (93). A similar titratable amino acid, histidine, is present in human TRPV6, which could mediate extracellular acid regulation of TRPV5/6 heteromeric channels in the DCT. It has been estimated that inhibition of TRPV5/6 caused by a decrease in lumen pH from 6.8 to 6.4 would lead to doubling of urinary Ca2+ excretion (93).

Familial hypomagnesemia with secondary hypocalcemia is an autosomal recessive disease characterized by renal wasting and defective intestinal absorption of Mg2+ and secondary hypocalcemia. Schlingmann et al. (31) and Walder et al. (32) reported that familial hypomagnesemia is caused by mutations of TRPM6. TRPM6 proteins are expressed in kidney and intestine, supporting the hypothesis that they are Mg2+ channels responsible for Mg2+ transport in these tissues. Transcellular reabsorption of Mg2+ in kidney occurs in DCT. A recent paper reported that TRPM6 is localized to the apical membrane of DCT in kidney and the brush border of the small intestine (94). Expression of TRPM6 in cultured HEK cells produces a Mg2+-permeable channel that is regulated by intracellular Mg2+ (94). TRPM6 contains an atypical kinase domain in the C-terminus (31,32⇓).

TRPM7 is ∼50% identical to TRPM6 and contains an atypical kinase domain as well (33,34⇓). TRPM7 is ubiquitous and conducts divalent cations, including Mg2+, Ca2+, and trace elements such as Mn2+ and Co2+ (95,96⇓). Cultured cells in which the TRPM7 gene has been inactivated have decreased viability, which can be rescued by supplementation of extracellular Mg2+ (34,97⇓). Mg2+ uptake through TRPM7 requires a functional coupling between its channel and kinase domain (97). Chubanov et al. (98) reported that TRPM6 and TRPM7 interact with each other to increase channel currents in cultured HEK cells. The authors suggested that TRPM6 and TRPM7 heteromultimers may form the functional epithelial Mg2+ channels. Mg2+ reabsorption in kidney and intestine is regulated by many hormones. It is tempting to speculate that hormonal regulation of TRPM6 (and TRPM7) involves its intrinsic kinase domain. Identification of TRPM6 (with or without TRPM7) as epithelial Mg2+ channels opens the door for future investigation of Mg2+ transport using cellular, molecular, and whole-animal genetic approaches.

Role of TRP in Cell Growth

Several TRP proteins have been found to play an important role in cell proliferation. TRPM1 is a tumor suppressor whose level of expression is inversely correlated with melanoma aggressiveness (21). TRPV6 is expressed in intestine and kidney and mediates transepithelial Ca2+ transport in these tissues. TRPV6 is normally undetectable in prostate tissue but is present at high levels in prostate cancer (99). Another TRP gene, TRPM8, is also upregulated in prostate cancer and in primary tumors of breast, colon, lung, and skin origin (100). Intracellular Ca2+ homeostasis plays a key role in cell-cycle control. An increase in intracellular Ca2+ caused by upregulation of TRPV6 or TRPM8 may trigger malignant transformation of cells. Alternatively, the increase in cellular uptake of Ca2+ may play a permissive role for rapid growth of tumor cells. As mentioned above, uptake of Mg2+ through TRPM7 is essential for cell survival in the physiologic culture media (34,97⇓). How TRPM1 suppresses tumor growth is currently unknown and requires future investigation.

Acknowledgments

I thank Drs. M. Baum and P. Igarashi for critical reading of the manuscript. Work in my laboratory is supported by National Institutes of Health Grants DK-20543, DK-54368, and DK-59530 and an Established Investigator Award (0440019N) from the American Heart Association.

C.-L.H. is holder of the Jacob Lemann Professorship in Calcium Transport of the University of Texas Southwestern Medical Center at Dallas.

  • © 2004 American Society of Nephrology

References

  1. ↵
    Cosens DJ, Manning A: Abnormal electroretinogram from a Drosophila mutant. Nature 224: 285–287, 1969
    OpenUrlCrossRefPubMed
  2. ↵
    Montell C, Rubin GM: Molecular characterization of the Drosophila trp locus: A putative integral membrane protein required for phototransduction. Neuron 2: 1313–1323, 1989
    OpenUrlCrossRefPubMed
  3. ↵
    Hardie RC, Ninke B: The trp gene is essential for a light-activated Ca2+ channel in Drosophila photoreceptors. Neuron 8: 643–651, 1992
    OpenUrlCrossRefPubMed
  4. ↵
    Montell C, Birnbaumer L, Flockerzi V, Bindels RJ, Bruford EA, Caterina MJ, Clapham DE, Harteneck C, Heller S, Julius D, Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, Schultz G, Shimizu N, Zhu MX: A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 92: 229–231, 2002
  5. ↵
    Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C: TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci U S A 92: 9652–9656, 1995
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Zhu X, Chu PB, Peyton M, Birnbaumer L: Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett 373: 193–198, 1995
    OpenUrlCrossRefPubMed
  7. ↵
    Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birbaumer L: TRP, a novel mammalian gene family essential for agonist-activated capacitance Ca2+ entry. Cell 85: 661–671, 1996
    OpenUrlCrossRefPubMed
  8. ↵
    Liman ER, Corey DP, Dulac C: TRP2: A candidate transduction channel for mammalian pheromone sensory signaling. Proc Natl Acad Sci U S A 96: 5791–5796, 1999
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Wissenbach U, Schroth G, Philipp S, Flockerza V: Structure and mRNA expression of a bovine trp homologue related to mammalian trp transcripts. FEBS Lett 429: 61–69, 1998
    OpenUrlCrossRefPubMed
  10. ↵
    Okada T, Inoue R, Yamazaki K, Maeda A, Kurosaki T, Yamakuni T, Tanaka I, Shimizu S, Ikenaka K, Imoto K, Mori Y: Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J Biol Chem 274: 27359–27370, 1999
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 389: 816–824, 1997
    OpenUrlCrossRefPubMed
  12. ↵
    Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D: A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398: 436–441, 1999
    OpenUrlCrossRefPubMed
  13. ↵
    Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y, DiStefano PS, Curtis R, Clapham DE: TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418: 181–186, 2002
    OpenUrlCrossRefPubMed
  14. ↵
    Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin JP, Ooi L, Egerton J, Charles KJ, Smart D, Randall AD, Anand P, Davis JB: TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418: 186–190, 2002
    OpenUrlCrossRefPubMed
  15. ↵
    Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P, Bevan S, Patapoutian A: A heat-sensitive TRP channel expressed in keratinocytes. Science 296: 2046–2049, 2002
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD: OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2: 695–702, 2000
    OpenUrlCrossRefPubMed
  17. ↵
    Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ: Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274: 8375–8378, 1999
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA: Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem 274: 22739–22746, 1999
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Colbert HA, Smith TL, Bargmann CI: OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J Neurosci 17: 8259–8269, 1997
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Tobin D, Madsen D, Kahn-Kirby A, Peckol E, Moulder G, Barstead R, Maricq A, Bargmann C: Combinatorial expression of TRPV channel proteins defines their sensory functions and subcellular localization in C. elegans neurons. Neuron 35: 307–318, 2002
    OpenUrlCrossRefPubMed
  21. ↵
    Duncan LM, Deeds J, Hunter J, Shao J, Holmgren LM, Woolf EA, Tepper RI, Shyjan AW: Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis. Cancer Res 58: 1515–1520, 1998
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F, Shimizu N: Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54: 124–131, 1998
    OpenUrlCrossRefPubMed
  23. ↵
    Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM: ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411: 595–599, 2001
    OpenUrlCrossRefPubMed
  24. ↵
    Sano Y, Inamura K, Miyake A, Mochizuki S, Yokoi H, Matsushime H, Furuichi K: Immunocyte Ca2+ influx system mediated by LTRPC2. Science 293: 1327–1730, 2001
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Perraud AL, Schmitz C, Scharenberg AM: TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium 33: 519–531, 2003
    OpenUrlCrossRefPubMed
  26. ↵
    Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K, Mori Y: LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell 9: 163–173, 2002
    OpenUrlCrossRefPubMed
  27. ↵
    Heiner I, Eisfeld J, Luckhoff A: Role and regulation of TRP channels in neutrophil granulocytes. Cell Calcium 33: 533–540, 2003
    OpenUrlCrossRefPubMed
  28. ↵
    Lee N, Chen J, Sun L, Wu S, Gray KR, Rich A, Huang M, Lin JH, Feder JN, Janovitz EB, Levesque PC, Blanar MA: Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3). J Biol Chem 278: 20890–20897, 2003
    OpenUrlAbstract/FREE Full Text
  29. ↵
    Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, Kinet JP: TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109: 397–407, 2002
    OpenUrlCrossRefPubMed
  30. ↵
    Hofmann T, Chubanov V, Gudermann T, Montell C: TRPM5 is a voltage-modulated and Ca(2+)-activated monovalent selective cation channel. Curr Biol 13: 1153–1158, 2003
    OpenUrlCrossRefPubMed
  31. ↵
    Schlingmann KP, Weber S, Peters M, Niemann-Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M: Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31: 166–170, 2002
    OpenUrlCrossRefPubMed
  32. ↵
    Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC: Mutation of TRPM6 causes familiar hypomagnesemia with secondary hypocalcemia. Nat Genet 31: 171–174, 2002
    OpenUrlCrossRefPubMed
  33. ↵
    Runnels LW, Yue L, Clapham DE: TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291: 1053–1047, 2001
    OpenUrl
  34. ↵
    Nadler MJS, Hermosura MC, Inabe K, Perraud A-L, Zhu Q, Stokes J, Kurosaki T, Kinet J-P, Penner R, Scharenberg AM, Fleig A: LTRPC7 is a MgATP-regulated divalent cation channel required for cell viability. Nature 411: 590–595, 2001
    OpenUrlCrossRefPubMed
  35. ↵
    Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M, Erdjument-Bromage H, Tempst P, Parmer TG, Prostko CR, Germino FJ, Hait WN: Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proc Natl Acad Sci U S A 94: 4884–4889, 1997
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Ryazanov AG: Elongation factor-2 kinase and its newly discovered relatives. FEBS Lett 514: 26–29, 2002
    OpenUrlCrossRefPubMed
  37. ↵
    McKemy DD, Neuhausser WM, Julius D: Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416: 52–58, 2002
    OpenUrlCrossRefPubMed
  38. ↵
    Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A: A TRP channel that senses cold stimuli and menthol. Cell 108: 705–715, 2002
    OpenUrlCrossRefPubMed
  39. ↵
    Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339–1342, 1996
    OpenUrlAbstract
  40. ↵
    Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP: Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96: 3934–3939, 1999
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S: Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4: 191–197, 2002
    OpenUrlCrossRefPubMed
  42. ↵
    Nomura H, Turco AE, Pei Y, Kalaydjieva L, Schiavello T, Weremowicz S, Ji W, Morton CC, Meisler M, Reeders ST, Zhou J: Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects. J Biol Chem 273: 25967–25973, 1998
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Veldhuisen B, Spruit L, Dauwerse HG, Breuning MH, Peters DJ: Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2). Eur J Hum Genet 7: 860–872, 1999
    OpenUrlCrossRefPubMed
  44. ↵
    Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millan JL, Gamble V, Harris PC: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10: 151–160, 1995
    OpenUrlCrossRefPubMed
  45. ↵
    Sandford R, Sgotto B, Aparicio S, Brenner S, Vaudin M, Wilson RK, Chissoe S, Pepin K, Bateman A, Chothia C, Hughes J, Harris P: Comparative analysis of the polycystic kidney disease 1 (PKD1) gene reveals an integral membrane glycoprotein with multiple evolutionary conserved. Hum Mol Genet 6: 1483–1489, 1997
    OpenUrlCrossRefPubMed
  46. ↵
    Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG: PKD1 interacts with PKD2 through probable coil-coil domain. Nat Genet 16: 179–183, 1997
    OpenUrlCrossRefPubMed
  47. ↵
    Littleton JT, Ganetzky B: Ion channels and synaptic organization: Analysis of the Drosophila genome. Neuron 26: 35–43, 2000
    OpenUrlCrossRefPubMed
  48. ↵
    Walker RG, Willingham AT, Zuker CS: A Drosophila mechanosensory transduction channel. Science 287: 2229–2234, 2000
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Sidi S, Friedrich RW, Nicolson T: NompC TRP channel required for vertebrate sensopry hair cell mechanotransduction. Science 301: 96–99, 2003
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS Jr, Bove C, Kaneski CR, Nagle J, Bromley MC, Colman M, Schiffmann R, Slaugenhaupt SA: Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9: 2471–2478, 2000
    OpenUrlCrossRefPubMed
  51. ↵
    Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G: Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet 67: 1110–1120, 2000
    OpenUrlCrossRefPubMed
  52. ↵
    Bargal R, Avidan N, Ben-Asher E, Olender Z, Zeigler M, Frumkin A, Raas-Rothschild A, Glusman G, Lancet D, Bach G: Identification of the gene causing mucolipidosis type IV. Nat Genet 26: 118–123, 2000
    OpenUrlCrossRefPubMed
  53. ↵
    Raychowdhury MK, Gonzalez-Perrett S, Montalbetti N, Timpanaro GA, Chasan B, Goldmann WH, Stahl S, Cooney A, Goldin E, Cantiello HF: Molecular pathophysiology of mucolipidosis type IV. pH dysregulation of the mucolipin-1 cation channel. Hum Mol Genet 13: 617–627, 2004
    OpenUrlCrossRefPubMed
  54. ↵
    Di Palma F, Belyantseva IA, Kim HJ, Vogt TF, Kachar B, Noben-Trauth K: Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc Natl Acad Sci U S A 99: 14994–14999, 2002
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Putney JW Jr: A model for receptor-regulated calcium entry. Cell Calcium 7: 1–12, 1986
    OpenUrlCrossRefPubMed
  56. ↵
    Parekh AB, Penner R: Store depletion and calcium influx. Physiol Rev 77: 901–930, 1997
    OpenUrlPubMed
  57. ↵
    Putney JR Jr, Mckay RR: Capacitance calcium entry channels. Bioessays 21: 38–46, 1999
    OpenUrlCrossRefPubMed
  58. ↵
    Liu X, Wang W, Singh BB, Lockwich T, Jadlowiec J, O’Connell B, Wellner R, Zhu MX, Ambudkar IS: Trp1, a candidate protein for the store-operated Ca(2+) influx mechanism in salivary gland cells. J Biol Chem 275: 3403–3411, 2000
    OpenUrlAbstract/FREE Full Text
  59. ↵
    Groschner K, Hingel S, Lintschinger B, Balzer M, Romanin C, Zhu X, Schreibmayer W: Trp proteins form store-operated cation channels in human vascular endothelial cells. FEBS Lett 437: 101–106, 1998
    OpenUrlCrossRefPubMed
  60. ↵
    Kiselyov K, Xu X, Mozhayeva G, Kuo T, Pessah I, Mignery G, Zhu X, Birnbaumer L, Muallem S: Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396: 478–482, 1998
    OpenUrlCrossRefPubMed
  61. ↵
    Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G, Hofmann F, Flockerzi V, Nilius B: Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nat Cell Biol 3: 121–127, 2001
    OpenUrlCrossRefPubMed
  62. ↵
    Riccio A, Mattei C, Kelsell RE, Medhurst AD, Calver AR, Randall AD, Davis JB, Benham CD, Pangalos MN: Cloning and functional expression of human short TRP7, a candidate protein for store-operated Ca2+ influx. J Biol Chem 277: 12302–12309, 2002
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Zitt C, Obukhov AG, Strubing C, Zobel A, Kalkbrenner F, Luckhoff A, Schultz G: Expression of TRPC3 in chinese hamster ovary cells results in calcium-activated cation currents not related to store depletion. J Cell Biol 138: 1333–1341, 1997
    OpenUrlAbstract/FREE Full Text
  64. ↵
    Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G: Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397: 259–263, 1999
    OpenUrlCrossRefPubMed
  65. ↵
    Acharya JK, Jalink K, Hardy RW, Hartenstein V, Zuker CS: InsP3 receptor is essential for growth and differentiation but not for vision in Drosophila. Neuron 18: 881–887, 1997
    OpenUrlCrossRefPubMed
  66. ↵
    Chyb S, Raghu P, Hardie RC: Polyunsaturated fatty acids activate the Drosophila light-sensitive channels TRP and TRPL. Nature 397: 255–259, 1999
    OpenUrlCrossRefPubMed
  67. ↵
    Hardie RC, Raghu P, Moore S, Juusola M, Baines RA, Sweeney ST: Calcium influx via TRP channels is required to maintain PIP2 levels in Drosophila photoreceptors. Neuron 30: 149–159, 2001
    OpenUrlCrossRefPubMed
  68. ↵
    Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D: The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21: 531–543, 1998
    OpenUrlCrossRefPubMed
  69. ↵
    Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED: Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400: 452–457, 1999
    OpenUrlCrossRefPubMed
  70. ↵
    Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U: Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 97: 6155–6160, 2000
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Guler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M: Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22: 6408–6414, 2002
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Nilius B, Vriens J, Prenen J, Droogmans G, Voets T: TRPV4 calcium entry channel: a paradigm for gating diversity. Am J Physiol 286: C195–C205, 2004
  73. ↵
    Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Anderson DA, Hwang SW, McIntyre T, Jegla T, Bevan S, Patapoutian A: ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112: 819–829, 2003
    OpenUrlCrossRefPubMed
  74. ↵
    Gillespie PG, Walker RG: Molecular basis of mechanosensory transduction. Nature 413: 194–202, 2001
    OpenUrlCrossRefPubMed
  75. ↵
    Sukharev SI, Blount P, Martinac B, Kung C: Mechanosensitive channels of Escherichia coli: The MscL gene, protein, and activities. Annu Rev Physiol 59: 633–657, 1997
    OpenUrlCrossRefPubMed
  76. ↵
    Liedtke W, Friedman JM: Abnormal osmotic regulation in trpv4-/- mice. Proc Natl Acad Sci U S A 100: 13698–13703, 2003
    OpenUrlAbstract/FREE Full Text
  77. ↵
    Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, Witman GB: Polycystin-2 localizes to cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol 12: R378–R380, 2002
    OpenUrlCrossRefPubMed
  78. ↵
    Yoder BK, Hou X, Guay-Woodford LM: The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13: 2508–2516, 2002
    OpenUrlAbstract/FREE Full Text
  79. ↵
    Praetorius HA, Spring KR: The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens 12: 517–520, 2003
    OpenUrlCrossRefPubMed
  80. ↵
    Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33: 129–137, 2003
    OpenUrlCrossRefPubMed
  81. ↵
    McGrath J, Somlo S, Makova S, Tian X, Brueckner M: Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114: 61–73, 2003
    OpenUrlCrossRefPubMed
  82. ↵
    Barr MM, Sternberg PM: A polycystic kidney-disease gene homologue required for male mating behavior in C. elegans. Nature 401: 386–389, 1999
    OpenUrlCrossRefPubMed
  83. ↵
    Barr MM, DeModena J, Braun D, Nguyen CQ, Hall DH, Sternberg PW: The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol 11: 1341–1346, 2001
    OpenUrlCrossRefPubMed
  84. ↵
    Gonzalez-Perrett S, Batelli M, Kim K, Essafi M, Timpanaro G, Moltabetti N, Reisin IL, Arnaout MA, Cantiello HF: Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity. J Biol Chem 277: 24959–24966, 2002
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG: Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 408: 990–994, 2000
    OpenUrlCrossRefPubMed
  86. ↵
    Vassilev PM, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, Babakhanlou H, Cruger G, Kanazirska M, Ye Cp, Brown EM, Hediger MA, Zhou J: Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease. Biochem Biophys Res Commun 282: 341–350, 2001
    OpenUrlCrossRefPubMed
  87. ↵
    Voets T, Nilius B: The pore of TRP channels: trivial or neglected? Cell Calcium 33: 299–302, 2003
    OpenUrlCrossRefPubMed
  88. ↵
    Liu D, Liman ER: Intracellular Ca2+ and phospholipid PIP2 regulate the taste transduction ion channel TRPM5. Proc Natl Acad Sci U S A 100: 15160–15165, 2003
    OpenUrlAbstract/FREE Full Text
  89. ↵
    Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ: Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J 22: 776–785, 2003
    OpenUrlAbstract
  90. ↵
    Nijenhuis T, Hoenderop JG, van der Kemp AW, Bindels RJ: Localization and regulation of the epithelial Ca2+ channel TRPV6 in the kidney. J Am Soc Nephrol 14: 2731–2740, 2003
    OpenUrlAbstract/FREE Full Text
  91. ↵
    Hoenderop JG, van Leeuwen JP, van der Eerden BC, Kersten FF, van der Kemp AW, Merillat AM, Waarsing JH, Rossier BC, Vallon V, Hummler E, Bindels RJ: Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 112: 1906–1914, 2003
    OpenUrlCrossRefPubMed
  92. ↵
    Sutton RA, Wong NL, Dirks JH: Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney. Kidney Int 15: 520–533, 1979
    OpenUrlCrossRefPubMed
  93. ↵
    Yeh B-I, Sun T-J, Lee J, Chen H-H, Huang C-L: Mechanism and molecular determinants for regulation of rabbit transient receptor potential type 5 (TRPV5) by extracellular pH. J Biol Chem 278: 51044–51052, 2003
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG: TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279: 19–25, 2004
    OpenUrlAbstract/FREE Full Text
  95. ↵
    Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A: TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121: 49–60, 2003
    OpenUrlAbstract/FREE Full Text
  96. ↵
    Kerschbaum HH, Kozak JA, Cahalan MD: Polyvalent cations as permeant probes of MIC and TRPM7 pores. Biophys J 84: 2293–2305, 2003
    OpenUrlCrossRefPubMed
  97. ↵
    Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM: Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 114: 191–200, 2003
    OpenUrlCrossRefPubMed
  98. ↵
    Chubanov V, Waldegger S, Mederos Y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T: Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci U S A 101: 2894–2899, 2004
    OpenUrlAbstract/FREE Full Text
  99. ↵
    Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V: Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem 276: 19461–19468, 2001
    OpenUrlAbstract/FREE Full Text
  100. ↵
    Tsavaler L, Shapero MH, Morkowski S, Laus R: Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res 61: 3760–3769, 2001
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 15 (7)
Journal of the American Society of Nephrology
Vol. 15, Issue 7
1 Jul 2004
  • Table of Contents
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
The Transient Receptor Potential Superfamily of Ion Channels
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
The Transient Receptor Potential Superfamily of Ion Channels
Chou-Long Huang
JASN Jul 2004, 15 (7) 1690-1699; DOI: 10.1097/01.ASN.0000129115.69395.65

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
The Transient Receptor Potential Superfamily of Ion Channels
Chou-Long Huang
JASN Jul 2004, 15 (7) 1690-1699; DOI: 10.1097/01.ASN.0000129115.69395.65
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Molecular Identification and Characterization of TRP Channels
    • Functions of TRP Channels
    • Acknowledgments
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Tubuloglomerular Feedback Synchronization in Nephrovascular Networks
  • How to Get Started with Single Cell RNA Sequencing Data Analysis
  • The Urine Anion Gap: Common Misconceptions
Show more Reviews

Cited By...

  • Optical Recording Reveals Novel Properties of GSK1016790A-Induced Vanilloid Transient Receptor Potential Channel TRPV4 Activity in Primary Human Endothelial Cells
  • HNF4{alpha} and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy
  • Milk Alkali Syndrome and the Dynamics of Calcium Homeostasis
  • Posttranslational Cleavage and Adaptor Protein Complex-dependent Trafficking of Mucolipin-1
  • Conformational changes of pore helix coupled to gating of TRPV5 by protons
  • The Foot Structure from the Type 1 Ryanodine Receptor Is Required for Functional Coupling to Store-operated Channels
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire