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Topical Review |
1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA 2Department of Physiology, UT South-Western Medical Center at Dallas, Dallas, TX 75390, USA
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(Received 14 August 2006;
accepted after revision 23 November 2006;
first published online 30 November 2006)
Corresponding author K. Kiselyov: Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA 15260, USA. Email: kiselyov{at}pitt.edu
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Introduction |
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The causal relationships between dysregulation of TRP channels and the corresponding genetic diseases remain obscure for several human TRPpathies. Some diseases, such as ADPKD, attracted enormous interest in recent years, which resulted in a significant degree of understanding of the physiology of the corresponding TRP channels if not of the exact connection between the channel dysregulation and the disease. As discussed below, the same is largely true for TRPC6, TRPV6 and cancer as well as for TRPC6 and FSG. Very limited information exists about localization, permeation properties or regulation of TRPM1, despite clearly documented links to skin cancer. Several recent reports, focused on the function of the lysosomal ion channel TRP-ML1, mutations in which are responsible for lysosomal storage disorder MLIV, have suggested several possible roles of this ion channel in regulating lysosomal function. The present review will focus on these TRPpathies, and will specifically discuss some unanswered questions pertaining to pathogenesis of these diseases and the roles of the corresponding ion channels in maintaining normal cellular function.
To illustrate the broad physiological roles of TRP channels, Table 1 lists the physiological functions of TRP channels derived from genetic diseases, in in vitro experiments and from knock-out mice. Additional information on the biology, physiological functions and therapeutic potential of TRP channels can be found in several excellent recent reviews (Clapham, 2003; Nilius et al. 2005) and a series of reviews published in Cell Calcium (volume 33, issues 5–6, 2003) and Pflugers Archiv (volume 451, number 1, 2005).
Mucolipin 1 and MLIV
MLIV is a neurodegenerative disorder with an early onset. Patients with MLIV display severe psychomotor retardation and a developmental delay (reviewed in Bach, 2001; Slaugenhaupt, 2002). Other clinical manifestations of MLIV include achloridia and hypergastrinaemia (Schiffmann et al. 1998; Lubensky et al. 1999). At the cellular level, MLIV is a classic lysosomal storage disease with accumulation, in virtually all tissues and cells, of electron-dense vesicles and membranous inclusions containing phospholipids (Bach & Desnick, 1988; Bargal & Bach, 1989) and gangliosides (Zeigler & Bach, 1986). Proteolysis defects have not been shown in MLIV.
MLIV is caused by nonsense or missense mutations in the gene MCOLN1, which codes for TRP-ML1, a member of the TRP-ML subfamily (Bassi et al. 2000; Sun et al. 2000). The mutations result in deletion or affect cellular localization or ion selectivity and permeability of TRP-ML1 (LaPlante et al. 2004; Manzoni et al. 2004; Raychowdhury et al. 2004; Cantiello et al. 2005; Kiselyov et al. 2005).
TRP-ML1 is a lysosomal ion channel (Manzoni et al. 2004; Kiselyov et al. 2005; Miedel et al. 2006; Soyombo et al. 2006; Vergarajauregui & Puertollano, 2006), and is therefore expected to regulate lysosomal ion content, although its role in lysosomal function is still not known in full. TRP-ML1 was reported to be a Ca2+ channel (LaPlante et al. 2002, 2004), or an outwardly rectifying monovalent cation channel regulated by either Ca2+ (Cantiello et al. 2005) or pH (Raychowdhury et al. 2004). Our recent work shows that TRP-ML1 limits lysosomal acidification by providing a lysosomal H+ leak pathway (Soyombo et al. 2006) (Fig. 1). H+ is a critical lysosomal ion that regulates numerous lysosomal functions. The acidification of the lysosomal lumen is mediated by a vacuolar H+ pump (Beyenbach & Wieczorek, 2006) and ClC family Cl– channels (Jentsch et al. 2005). A H+ leak mechanism that limits lysosomal acidification has been proposed but not identified. We suggest that in the absence of TRP-ML1 the lysosomes are chronically overacidified. In contrast with our findings, Bach et al. (1999) reported normal lysosomal pH in MLIV fibroblasts. The reason for the different findings is not known. However, we note that (a) we used two different techniques to estimate lysosomal pH, (b) MLIV cells are particularly sensitive to the weak base chloroquine (Goldin et al. 1999; Soyombo et al. 2006), which can only be if their lysosomes are more acidic than the normal lysosomes, (c) TRP-ML1 is permeable to H+ and (d), the MLIV phenotype can be reversed by dissipating lysosomal pH (Soyombo et al. 2006).
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Polycystin 2 and ADPKD
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited late onset renal disorder characterized by formation of kidney cysts leading to renal failure. ADPKD also has extrarenal effects that include formation of cysts in the pancreas, liver and spleen, hypertension and brain aneurisms. About 20% of the cases of ADPKD are associated with mutations in the gene PKD2, which codes for the ion channel polycystin 2 (TRPP2) (reviewed in Koptides & Deltas, 2000; Boucher & Sandford, 2004). TRPP2 physically interacts with polycystin 1 (PC1), which is probably involved in cell–cell communication and establishment of cellular junctions. Mutations in the gene coding for PC1 are responsible for the remaining cases of ADPKD.
TRPP2 is a cation channel with limited selectivity for Ca2+ (Gonzalez-Perrett et al. 2001; Koulen et al. 2002). Depending on cell type and expression system, TRPP2 localizes at the endoplasmic reticulum (Koulen et al. 2002), the primary cilia (Yoder et al. 2002; Nauli et al. 2003; Raychowdhury et al. 2005; Geng et al. 2006), the apical pole (Gonzalez-Perrett et al. 2001) or the basolateral surface of epithelial cells (Foggensteiner et al. 2000).
Why mutations in TRPP2 lead to formation of the fluid-filled kidney cysts is unclear. Localization of TRPP2 in the primary cilia led to a model in which TRPP2 reads the mechanical disturbance of the cilial apparatus in response to flow (Nauli et al. 2003; Ong & Wheatley, 2003; Nauli & Zhou, 2004). TRPP2 responds to mechanical stimulation (Montalbetti et al. 2005) and the association of TRPP2 with the cytoskeletal elements tropomyosin-1 (Li et al. 2003a), troponin I (Li et al. 2003b), 
-actinin (Li et al. 2005a) and HS1-Associated Protein X1 (Hax-1) Gallagher et al. 2000) further supports the role of TRPP2 in mechanotransduction. The sensitivity of TRPP2 to mechanical stimuli is probably regulated by hormones, neurotransmitters and growth factors since stimulation of phospholipase C-coupled receptors activates TRPP2 (Ma et al. 2005).
The mechanotransduction model postulates that activation of TRPP2 by mechanical deflection of the cilia induces local Ca2+ influx, which propagates into the cell interior by Ca2+-induced Ca2+ release through activation of ryanodine- and inositol (1,4,5) trisphosphate receptors (Nauli et al. 2003), or perhaps by activation of the endoplasmic reticulum resident TRPP2 (Koulen et al. 2002). The flow-induced Ca2+ responses in tubular epithelial cells mediated by TRPP2 are probably necessary for reporting changes in flow rate and fluid osmolarity. This can explain the particular susceptibility to ADPKD of the kidney, pancreatic and biliary duct and spleen, all of which experience large fluctuations in fluid flow and osmolarity.
How the TRPP2-mediated Ca2+ fluxes translate to the downstream cellular response has not been elucidated. The TRPP2-mediated Ca2+ fluxes probably have acute and long-term effects. The latter may include gene activation and regulation of cell proliferation.
TRPP2 was shown to be a cofactor in PC-1-dependent cell cycle arrest induced by activation of the JAK-STAT signalling pathway (Bhunia et al. 2002). Furthermore, the C terminus of TRPP2 binds the transcriptional suppressor Id2 (Li et al. 2005b), a member of an ‘inhibitor of DNA binding’ (Id) helix–loop–helix transcription factor subfamily. The Id family proteins lack DNA binding domains but they bind helix–loop–helix transcription factors, and inhibit their binding to DNA. Depending on cell type, this may inhibit or promote cell differentiation and proliferation (reviewed in Perk et al. 2005). In the absence of TRPP2 or PC1 most of Id2 is found in the nucleus. TRPP2 sequesters Id2 in the cytosol (Li et al. 2005b), which up-regulates a cyclin-dependent kinase (CDK) inhibitor p21 and down-regulates Cdk2. These findings suggest that the predominantly nuclear localization of Id2 in TRPP2- (or PC1-) deficient cells affects the p21-CDK cell cycle regulation cascade and results in aberrant cell growth (Li et al. 2005b). The role of TRPP2 Ca2+ transport function in either of these processes is unknown. Both effects, however, can account for the inverse relation between the levels of TRPP2 in kidney tissues and cell growth rates (Chang et al. 2006; Grimm et al. 2006).
Melastatin and cutaneous melanomas
A search for molecular correlates of the metastatic potential of human cutaneous melanomas has led to the identification of another TRP member, melastatin 1 (TRPM1). A loss of TRPM1 mRNA in metastasizing skin cancer is as robust a predictor of melanoma progression as any of the commonly accepted criteria (Duncan et al. 1998).
Normal and benign melanocytes express the full-length TRPM1 mRNA of approximately 5.4 kb along with some shorter products (Duncan et al. 1998; Fang & Setaluri, 2000). Metastatic melanomas and pigmented metastatic melanoma cell lines lack the full-length transcript, but express several short fragments of TRPM1 mRNA (Duncan et al. 1998; Fang & Setaluri, 2000). The anticancer drug hexamethylene bisacetamide (HMBA) reverses the loss of the full-length TRPM1 mRNA (Fang & Setaluri, 2000). Although the latter observation links melanoma progression to the loss of TRPM1, it does not establish a causative relation between the two.
TRPM1 mRNA levels in melanocytes and melanoma cell lines seem to depend on the melanocyte-specific transcription factor MITF as the TRPM1 promoter is under the MITF control and overexpression of MITF increases expression of TRPM1 (Miller et al. 2004; Zhiqi et al. 2004).
The channel properties and physiological function of TRPM1 have not been explored methodically. The only recording of TRPM1 activity was obtained with recombinant channel expressed in HEK 293 cells, where expression of the full-length TRPM1 dramatically increased resting [Ca2+]i (Xu et al. 2001). When expressed alone, the full-length channel was targeted to the plasma membrane, while coexpression of the full-length and the short isoforms resulted in retainment of the full-length TRPM1 in the endoplasmic reticulum (Xu et al. 2001). It is currently unknown whether expression of TRPM1 in metastasizing lines inhibits their growth. The situation is further complicated by the fact that the native TRPM1 protein has not been identified and it was reported that normal melanocytes do not express noticeable levels of the predicted full-length TRPM1. A series of smaller products is detected instead, which was attributed to proteolysis of the full length protein (Zhiqi et al. 2004).
The properties and cellular localization of other TRP channels involved in cancer are somewhat better established. TRPC6 is a plasma membrane channel permeable to monovalent cations, modestly selective for Ca2+ and involved in Ca2+ influx induced by activation of G protein-coupled receptors (Estacion et al. 2004, 2006). TRPC6 was reported to be down-regulated in a murine autocrine tumour model (Buess et al. 1999) and to mediate the Ca2+ influx that maintains growth of prostate cancer epithelial cells (Thebault et al. 2006).
The highly Ca2+-selective TRP channel, TRPV6, a vanilloid receptor homologue, is up-regulated in prostate cancer (Peng et al. 2001; Wissenbach et al. 2001, 2004; Fixemer et al. 2003; Schwarz et al. 2006) and in breast, thyroid, colon, and ovarian carcinomas (Zhuang et al. 2002). Chronic overexpression of TRPV6 reversibly increases proliferation of HEK 293 cells (Schwarz et al. 2006).
Another TRP channel associated with cancer is TRPM8. TRPM8 is a non-selective cation channel, that mediates cold sensation and response to menthol in neuronal cells (Peier et al. 2002) is also up-regulated in prostate cancer (Tsavaler et al. 2001; Fuessel et al. 2003; Henshall et al. 2003; Zhang & Barritt, 2006). Strikingly, TRPM8 seems to be lost at the very advanced stages of prostate cancer (Henshall et al. 2003). TRPM8 expression is regulated by androgen (Henshall et al. 2003; Zhang & Barritt, 2004; Bidaux et al. 2005) and is required for the survival of the androgen-sensitive LNCaP cell line (Zhang & Barritt, 2004).
Although a connection between apoptosis, cancer and [Ca2+]i has been established, it is not clear why up- or down-regulation of these specific TRP channels induce cell transformation towards the cancerous phenotype. The remarkable plasticity of the cellular Ca2+ signalling machinery (Zhao et al. 2001) would probably allow the cells to adapt to a change in TRP channel activity in order to maintain normal Ca2+ signalling. It is likely that these TRP channels have a specific role in a regulatory protein complex in which they reside. For example, by colocalizing at the cell junctional complexes, TRP channels may participate in the regulation of cell adhesion and neighbour sensing. Studying the role of the cancer-associated TRP channels in their cellular context should test these possibilities.
TRPC6 and familial focal segmental glomerulosclerosis
Recent studies linked mutations in TRPC6 to familial focal segmental glomerulosclerosis (FSG), a form of nephropathy due to aberrant glomerular filtration (Reiser et al. 2005; Winn et al. 2005). FSG causes proteinuria, nephritic syndrome and a progressive loss of renal function, often resulting in end-stage renal disease (Daskalakis & Winn, 2006). Glomerular filtration is regulated by the slit diaphragm, which forms the renal filtration barrier. The glomerular podocytes with their foot processes are central component of the slit diaphragm (Somlo & Mundel, 2000). The podocytes are contractile cells that actively regulate glomerular permeability. Several structural proteins of podocytes participate in assembly or regulation of the slit diaphragm. Among them are nephrin, a 185 kDa single transmembrane spanning protein, localizing at signalling domains in the podocyte foot structure (Ruotsalainen et al. 1999) and podocin, a 42 kDa single transmembrane spanning protein that is found at the base of the podocyte foot structure (Roselli et al. 2002). Podocin interacts with nephrin and with a CD2-associated protein CD2AP (Schwarz et al. 2001). Mutations in these structural proteins and in -actinin 4 (Mathis et al. 1998; Kaplan et al. 2000) have been linked to the familial forms of FSG. Mutations in NPHS1 that codes for nephrin and in NPHS2 that codes for podocin are responsible for the autosomal recessive forms of FSG (Kestila et al. 1998), whereas mutations in ACTN4 coding for -actinin 4 cause autosomal dominant form of FSG (Mathis et al. 1998).
Another autosomal dominant form of FSG was, unexpectedly, linked to mutations in TRPC6. In the glomerulus, TRPC6 is expressed at high levels in the podocyte foot structure, which determines glomerular permeability to macromolecules, including proteins. In the podocytes, TRPC6 interacts with nephrin and podocin, but not with CD2AP (Reiser et al. 2005; Winn et al. 2005). Mutations in TRPC6 associated with FSG were found in several cohorts and appear to fall into two categories: mutations that result in channel activation (Reiser et al. 2005; Winn et al. 2005), and mutations that had no apparent effect on channel activity (Reiser et al. 2005). The activating mutation P112Q was shown to increase the surface expression of TRPC6 (Reiser et al. 2005; Winn et al. 2005). The mechanism by which the R895C and E897K increase TRPC6 activity is not known.
It is possible that the activating mutations in TRPC6 result in an increased basal [Ca2+]i to cause a tonic contraction of the podocytes and a persistent increase in glomerular permeability to macromolecules. The cause and effect for the mutations that do not increase TRPC6 activity is still to be determined. These mutations may boost TRPC6 sensitivity to stimulation, alter protein turnover or alter interaction with nephrin, podocin or with other TRPC channels. Podocytes express TRPC1, TRPC5 and TRPC6 (Reiser et al. 2005). TRPC6 function within a hetero-multimeric TRPC channels complex (Strubing et al. 2003; Bandyopadhyay et al. 2005; Dietrich et al. 2005a). It is thus possible that mutations that did not affect the activity of heterologously expressed TRPC6 may affect Ca2+ influx when TRPC6 is present in hetero-multimers.
It is unclear why some of the probands analysed by Reiser et al. were positive for such mutations, but did not show the kidney pathology (Reiser et al. 2005). The latter, and the lack of a clear kidney phenotype in the TRPC6 knock-out mice (Dietrich et al. 2005b), suggests that an unidentified genetic modifier is also involved in FSG pathogenesis. Indeed, it has been known since the 1970s that a circulating humoral factor is associated with FSG (Shalhoub, 1974). The involvement of a circulating factor was postulated based on the observations of recurrent proteinuria in transplant patients who were diagnosed with FSG (Ohta et al. 2001), induction of proteinuria in rats injected with serum from patients with FSG (Zimmerman, 1984) and remission of the proteinuria by removal of serum proteins by treatment with protein A–Sepharose (Dantal et al. 1994). It is possible that variations in the levels of the circulating factors between patients or with time may account for variability of manifestations of the disease and its timing among patients carrying mutations in TRPC6.
In conclusion, several human diseases highlight the key role that TRP channels play in cellular physiology. Tracing mutations in ion channels that are associated with human diseases provides an excellent tool to reveal their cellular function. Such studies can also identify the signalling pathway that interprets signals initialed by the ion channels in the specific cellular environment in which they function. An invaluable advantage of these systems is that they have very distinct phenotypes, which facilitates testing novel models and hypotheses.
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