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At least 19 recordsLinked to original sources
PubMed2005

TRP channels in disease.

The mammalian TRP (transient receptor potential) family consists of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. These subfamilies encompass 28 ion channels that function as diverse cellular sensors. All of the channels are permeable to monovalent cations, and most are also permeable to Ca(2+). There are strong indications that TRP channels are involved in many diseases. At this point, four channelopathies have been identified in which a defect in a TRP channel-encoding gene is the direct cause of disease. TRPs are also involved in some systemic diseases because of their role as receptors for irritants, inflammation products, and xenobiotic toxins. Other indications of the involvement of TRPs in several diseases come from correlations between the levels of channel expression and disease symptoms or from the mapping of TRP-encoding genes to susceptible chromosome regions. Finally, the phenotypes of TRP knockout mice and other transgenic models allow a degree of extrapolation to human diseases. We present an overview of current knowledge about the role of TRP channels in human disease and highlight some TRP "suspects" for which a role in disease can be anticipated. An understanding of the genetics of disease may lead to the development of targeted new therapies.

Animals↗
PubMed2004

Assembly and gating of TRPC channels in signalling microdomains.

A variety of plasmalemmal Ca2+-permeable channels, many of which are assembled from TRPC channels and are regulated by elements of the phosphatidylinositol pathway, may fulfil the role of store-operated channels (SOCs) and receptor-operated channels (ROCs). Growing evidence suggests that TRPC channels are clustered into spatially restricted microdomains that are important interaction sites for signalling molecules and for the induction of selective cellular responses. For example, TRPC1, which is activated solely by the depletion of internal stores in neurons, is assembled in a Ca2+ signalling complex, composed of the bradykinin receptor, G alpha(q) subunit, phospholipase C (PLC)beta and inositol 1,4,5-trisphosphate receptor (IP3R) whereas TRPC6, which is activated by phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis per se, is evenly distributed. Thus, differential targeting of TRPCs in microdomains allows different receptors to selectively recruit different Ca2+ entry pathways. TRPCs also co-assemble with members of the TRPP group, the polycystins. Because the polycystin proteins are thought to function as sensors of the extracellular environment, it can be hypothesized that TRPC channels are involved in a wide range of cellular functions other than those of SOCs and ROCs, including mechanotransduction.

Animals↗
PubMed2006

Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor.

Animals use their gustatory systems to evaluate the nutritious value, toxicity, sodium content, and acidity of food. Although characterization of molecular identities that receive taste chemicals is essential, molecular receptors underlying sour taste sensation remain unclear. Here, we show that two transient receptor potential (TRP) channel members, PKD1L3 and PKD2L1, are coexpressed in a subset of taste receptor cells in specific taste areas. Cells expressing these molecules are distinct from taste cells having receptors for bitter, sweet, or umami tastants. The PKD2L1 proteins are accumulated at the taste pore region, where taste chemicals are detected. PKD1L3 and PKD2L1 proteins can interact with each other, and coexpression of the PKD1L3 and PKD2L1 is necessary for their functional cell surface expression. Finally, PKD1L3 and PKD2L1 are activated by various acids when coexpressed in heterologous cells but not by other classes of tastants. These results suggest that PKD1L3 and PKD2L1 heteromers may function as sour taste receptors.

Calcium↗
PubMed1999

Specific association of the gene product of PKD2 with the TRPC1 channel.

The function(s) of the genes (PKD1 and PKD2) responsible for the majority of cases of autosomal dominant polycystic kidney disease is unknown. While PKD1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cell-cell or cell-matrix interactions, PKD2 has homology to PKD1 and the major subunit of the voltage-activated Ca2+ channels. We now describe sequence homology between PKD2 and various members of the mammalian transient receptor potential channel (TRPC) proteins, thought to be activated by G protein-coupled receptor activation and/or depletion of internal Ca2+ stores. We show that PKD2 can directly associate with TRPC1 but not TRPC3 in transfected cells and in vitro. This association is mediated by two distinct domains in PKD2. One domain involves a minimal region of 73 amino acids in the C-terminal cytoplasmic tail of PKD2 shown previously to constitute an interacting domain with PKD1. However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1. The C-terminal domain is sufficient but not necessary for the PKD2-TRPC1 association. A more N-terminal domain located within transmembrane segments S2 and S5, including a putative pore helical region between S5 and S6, is also responsible for the association. Given the ability of the TRPC to form functional homo- and heteromultimeric complexes, these data provide evidence that PKD2 may be functionally related to TRPC proteins and suggest a possible role of PKD2 in modulating Ca2+ entry in response to G protein-coupled receptor activation and/or store depletion.

Amino Acid Sequence↗
PubMed2005

Characterization of single channel currents from primary cilia of renal epithelial cells.

The primary cilium is a ubiquitous, non-motile microtubular organelle lacking the central pair of microtubules found in motile cilia. Primary cilia are surrounded by a membrane, which has a unique complement of membrane proteins, and may thus be functionally different from the plasma membrane. The function of the primary cilium remains largely unknown. However, primary cilia have important sensory transducer properties, including the response of renal epithelial cells to fluid flow or mechanical stimulation. Recently, renal cystic diseases have been associated with dysfunctional ciliary proteins. Although the sensory properties of renal epithelial primary cilia may be associated with functional channel activity in the organelle, information in this regard is still lacking. This may be related to the inherent difficulties in assessing electrical activity in this rather small and narrow organelle. In the present study, we provide the first direct electrophysiological evidence for the presence of single channel currents from isolated primary cilia of LLC-PK1 renal epithelial cells. Several channel phenotypes were observed, and addition of vasopressin increased cation channel activity, which suggests the regulation, by the cAMP pathway of ciliary conductance. Ion channel reconstitution of ciliary versus plasma membranes indicated a much higher channel density in cilia. At least three channel proteins, polycystin-2, TRPC1, and interestingly, the alpha-epithelial sodium channel, were immunodetected in this organelle. Ion channel activity in the primary cilium of renal cells may be an important component of its role as a sensory transducer.

Animals↗
PubMed2005

Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2).

Mucolipins (transient receptor potential mucolipin, TRPML) and polycystin-2 proteins (transient receptor potential polycystin, TRPP) constitute two small families of cation channels with motif and sequence similarities to the transient receptor potential (TRP) class of non-selective cation channels. Genetic defects in TRPML1 and TRPML3 in humans and in animal models cause the accumulation of large vacuoles, leading to a variety of cellular phenotypes including neurological and neurosensory deficiencies. TRPML1 is a Ca(2+)-, K(+)-, and Na(+)-permeable cation channel sensitive to pH changes, and regulates a critical step in the maturation of late endosomes to lysosomes. Mutations of TRPP2 in humans result in autosomal dominant polycystic kidney disease. Molecular studies have demonstrated that TRPP2 and TRPP3 proteins function as Ca(2+)-regulated, non-selective cation channels. During embryogenesis TRPP2 is active in node monocilia and plays a role in the establishment of left-right asymmetry. Recent results have indicated that TRPP2 interacts with polycystin-1 and that their interaction is important for their function as mechanosensitive channels at the primary cilium of renal epithelial cells. The interaction of polycystin family members appears to be conserved and is critical for fertilization and mating behavior. An emerging concept from the studies of the polycystin family is that they function as cation-influx based devices for sensing extracellular signals on ciliated structures. Here we review the function of TRPML1 and TRPP2 as representative members of these families, focusing on the genetics, physiology, and biochemistry.

Animals↗
PubMed2004

Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility.

Humans heterozygous for PKD1 or PKD2 develop autosomal dominant polycystic kidney disease, a common genetic disorder characterized by renal cyst formation and extrarenal complications such as hypertension and vascular aneurysms. Cyst formation requires the somatic inactivation of the wild type allele. However, it is unknown whether this recessive mechanism applies to life-threatening vascular aneurysms, which could involve weakening of the endothelial lining or surrounding vascular smooth muscle cells (SMCs). Drosophila Pkd2 at 33E3 (Pkd2) encodes a PKD2 family of Ca(2+)-activated Ca(2+)-permeable cation channels. We show here that loss-of-function Pkd2 mutations severely reduced the contractility of the visceral SMCs, which was restored by expressing wild type Pkd2 cDNA via a muscle-specific Gal4 driver. The effect of Pkd2 mutations alone on the skeletal muscle was minimal but was exacerbated by ryanodine-induced perturbation of intracellular Ca(2+) stores. Consistent with this, Pkd2 interacted strongly with a ryanodine receptor mutation, causing a synergistic reduction of larval body wall contraction rate that is normally regulated through Ca(2+) oscillation during excitation-contraction coupling in the skeletal muscle. These results suggest that PKD2 cooperates with the ryanodine receptor to promote optimal muscle contractility through intracellular Ca(2+) homeostasis. Further genetic analysis indicated that Pkd2 is strongly haploinsufficient for normal SMC contractility. Since Ca(2+) homeostasis is a conserved mechanism for optimal muscle performance, our results raise the possibility that inactivation of just one PKD2 copy is sufficient to compromise vascular SMC contractility and function in PKD2 heterozygous patients, thus explaining their increased susceptibility to hypertension and vascular aneurysms.

Animals↗
PubMed1996

PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

Amino Acid Sequence↗
PubMed2003

Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.

Animals↗
PubMed2004

Polycystin-1 activates the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway.

Regulation of intracellular Ca(2+) mobilization has been associated with the functions of polycystin-1 (PC1) and polycystin-2 (PC2), the protein products of the PKD1 and PKD2 genes. We have now demonstrated that PC1 can activate the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway through Galpha(q) -mediated activation of phospholipase C (PLC). Transient transfection of HEK293T cells with an NFAT promoter-luciferase reporter demonstrated that membrane-targeted PC1 constructs containing the membrane proximal region of the C-terminal tail, which includes the heterotrimeric G protein binding and activation domain, can stimulate NFAT luciferase activity. Inhibition of glycogen synthase kinase-3beta by LiCl treatment further increased PC1-mediated NFAT activity. PC1-mediated activation of NFAT was completely inhibited by the calcineurin inhibitor, cyclosporin A. Cotransfection of a construct expressing the Galpha(q) subunit augmented PC1-mediated NFAT activity, whereas the inhibitors of PLC (U73122) and the inositol trisphosphate and ryanodine receptors (xestospongin and 2-aminophenylborate) and a nonspecific Ca(2+) channel blocker (gadolinium) diminished PC1-mediated NFAT activity. PC2 was not able to activate NFAT. An NFAT-green fluorescent protein nuclear localization assay demonstrated that PC1 constructs containing the C-tail only or the entire 11-transmembrane spanning region plus C-tail induced NFAT-green fluorescent protein nuclear translocation. NFAT expression was demonstrated in the M-1 mouse cortical collecting duct cell line and in embryonic and adult mouse kidneys by reverse transcriptase-PCR and immunolocalization. These data suggest a model in which PC1 signaling leads to a sustained elevation of intracellular Ca(2+) mediated by PC1 activation of Galpha(q) followed by PLC activation, release of Ca(2+) from intracellular stores, and activation of store-operated Ca(2+) entry, thus activating calcineurin and NFAT.

Active Transport, Cell Nucleus↗
PubMed2005

Polycystin-2 accelerates Ca2+ release from intracellular stores in Caenorhabditis elegans.

Polycystin-2, a member of the TRP family of calcium channels, is encoded by the human PKD2 gene. Mutations in that gene can lead to swelling of nephrons into the fluid-filled cysts of polycystic kidney disease. In addition to expression in tubular epithelial cells, human polycystin-2 is found in muscle and neuronal cells, but its cell biological function has been unclear. A homologue in Caenorhabditis elegans is necessary for male mating behavior. We compared the behavior, calcium signaling mechanisms, and electrophysiology of wild-type and pkd-2 knockout C. elegans. In addition to characterizing PKD-2-mediated aggregation and mating behaviors, we found that polycystin-2 is an intracellular Ca(2+) release channel that is required for the normal pattern of Ca(2+) responses involving IP(3) and ryanodine receptor-mediated Ca(2+) release from intracellular stores. Activity of polycystin-2 creates brief cytosolic Ca(2+) transients with increased amplitude and decreased duration. Polycystin-2, along with the IP(3) and ryanodine receptors, acts as a major calcium-release channel in the endoplasmic reticulum in cells where rapid calcium signaling is required, and polycystin-2 activity is essential in those excitable cells for rapid responses to stimuli.

Amino Acid Sequence↗
PubMed2006

Nonspecific cation current associated with native polycystin-2 in HEK-293 cells.

Mutations in either PKD1 or PKD2 gene are associated with autosomal dominant polycystic kidney disease, the most common inherited kidney disorder. Polycystin-2 (PC2), the PKD2 gene product, and the related protein polycystin-L, function as Ca(2+)-permeable, nonselective cation channels in different expression systems. This work describes a nonspecific cation current (I(CC)) that is present in native HEK-293 cells and highly associated with a PC2-channel activity. The current is voltage dependent, activating for potentials that are positive to -50 mV and inactivating in a few milliseconds. It is sensitive to Cd(2+), Gd(3+), La(3+), SKF96365, and amiloride. After silencing of PC2 by RNA interfering, cells show a reduced current that is restored by transfection with normal but not truncated PC2. Consistently, I(CC) is abolished by perfusion with an anti-PC2 antibody. Furthermore, heterologous expression of the PC1 cytoplasmic tail significantly increases I(CC) peak amplitude compared with native cells. This is the first characterization of such a current in HEK-293 cells, a widely used expression system for ion channels. These cells, therefore, could be regarded as a suitable and readily accessible tool to study interactions between native PC2/PC1 complex and other membrane proteins, thus contributing to the understanding of autosomal dominant polycystic kidney disease pathogenesis.

Cation Transport Proteins↗
PubMed2004

Regulation of calcium signaling by polycystin-2.

Autosomal dominant PKD (ADPKD) is a common lethal genetic disorder characterized by progressive development of fluid-filled cysts in the kidney and other target organs. ADPKD is caused by mutations in the PKD1 and PKD2 genes, encoding the transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Although the function and putative interacting ligands of PC1 are largely unknown, recent evidence indicates that PC2 behaves as a TRP-type Ca(2+)-permeable nonselective cation channel. The PC2 channel is implicated in the transient increase in cytosolic Ca(2+) in renal epithelial cells and may be linked to the activation of subsequent signaling pathways. Recent studies also indicate that PC1 functionally interacts with PC2 such that the PC1-PC2 channel complex is an obligatory novel signaling pathway implicated in the transduction of environmental signals into cellular events. The present review purposely avoids issues of regulation of PC2 expression and trafficking and focuses instead on the evidence for the TRP-type cation channel function of PC2. How its role as a cation channel may unmask mechanisms that trigger Ca(2+) transport and regulation is the focus of attention. PC2 channel function may be essential in renal cell function and kidney development. Nonrenal-targeted expression of PC2 and related proteins, including the cardiovascular system, also suggests previously unforeseeable roles in signal transduction.

Animals↗
PubMed2006

Two members of the TRPP family of ion channels, Pkd1l3 and Pkd2l1, are co-expressed in a subset of taste receptor cells.

Taste receptors cells are responsible for detecting a wide variety of chemical stimuli. Several molecules including both G protein coupled receptors and ion channels have been shown to be involved in the detection and transduction of tastants. We report on the expression of two members of the transient receptor potential (TRP) family of ion channels, PKD1L3 and PKD2L1, in taste receptor cells. Both of these channels belong to the larger polycystic kidney disease (PKD or TRPP) subfamily of TRP channels, members of which have been demonstrated to be non-selective cation channels and permeable to both Na(+) and Ca(2+). Pkd1l3 and Pkd2l1 are co-expressed in a select subset of taste receptor cells and therefore may, like other PKD channels, function as a heteromer. We found the taste receptor cells expressing Pkd1l3 and Pkd2l1 to be distinct from those that express components of sweet, bitter and umami signal transduction pathways. These results provide the first evidence for a role of TRPP channels in taste receptor cell function.

Amino Acid Sequence↗
PubMed2004

The N-terminal extracellular domain is required for polycystin-1-dependent channel activity.

Autosomal dominant polycystic kidney disease (PKD) is caused by mutation of polycystin-1 or polycystin-2. Polycystin-2 is a Ca(2+)-permeable cation channel. Polycystin-1 is an integral membrane protein of less defined function. The N-terminal extracellular region of polycystin-1 contains potential motifs for protein and carbohydrate interaction. We now report that expression of polycystin-1 alone in Chinese hamster ovary (CHO) cells and in PKD2-null cells can confer Ca(2+)-permeable non-selective cation currents. Co-expression of a loss-of-function mutant of polycystin-2 in CHO cells does not reduce polycystin-1-dependent channel activity. A polycystin-1 mutant lacking approximately 2900 amino acids of the extracellular region is targeted to the cell surface but does not produce current. Extracellular application of antibodies against the immunoglobulin-like PKD domains reduces polycystin-1-dependent current. These results support the hypothesis that polycystin-1 is a surface membrane receptor that transduces the signal via changes in ionic currents.

Animals↗
PubMed2002

Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity.

Polycystin-2, the product of the human PKD2 gene, whose mutations cause autosomal dominant polycystic kidney disease, is a large conductance, Ca(2+)-permeable non-selective cation channel. Polycystin-2 is functionally expressed in the apical membrane of the human syncytiotrophoblast, where it may play a role in the control of fetal electrolyte homeostasis. Little is known, however, about the mechanisms that regulate polycystin-2 channel function. In this study, the role of pH in the regulation of polycystin-2 was assessed by ion channel reconstitution of both apical membranes of human syncytiotrophoblast and the purified FLAG-tagged protein from in vitro transcribed/translated material. A kinetic analysis of single channel currents, including dwell time histograms, confirmed two open and two close states for spontaneous channel behavior and a strong voltage dependence of the open probability of the channel (P(o)). A reduction of cis pH (pH(cis)) decreased P(o) and shifted the voltage dependence of channel function but had no effect on the single channel conductance. An increase in pH(cis), in contrast, increased NP(o) (channel number times P(o)). Elimination of the H(+) chemical gradient did not reverse the low pH(cis) inhibition of polycystin-2. Similar findings confirmed the pH effect on the in vitro translated, FLAG-tagged purified polycystin-2. The data indicate the presence of an H(+) ion regulatory site in the channel protein, which is accessible from the cytoplasmic side of the protein. This protonation site controls polycystin-2 cation-selective channel activity.

Female↗
PubMed2002

Do polycystins function as cation channels?

PURPOSE OF REVIEW: During the past 2 years growing evidence has emerged that polycystins (polycystin-1 and polycystin-2) are ion channels or regulators of ion channels. This suggests that autosomal-dominant polycystic kidney disease (ADPKD), which arises from mutations in polycystins, is a form of ion-channel disease (channelopathy). The present review addresses the properties and the mode of action of polycystin channels; it also discusses how polycystin channel signaling may be involved in cyst formation in ADPKD. RECENT FINDINGS: The precise functions of polycystin-1 and polycystin-2 are unclear. However, recent work has revealed that polycystin-1 may induce or modulate ion channels, including polycystin-2 channels, and that polycystin-2 functions as a calcium-regulated, calcium-permeable cation channel on the endoplasmic reticulum or on the plasma membrane with polycystin-1. These data suggest that ion-channel signaling mediated by polycystins is important for tubule formation in kidney and that disrupted signaling results in cyst formation. SUMMARY: ADPKD is a systemic hereditary disease that is characterized by renal and hepatic cysts, and results in end-stage renal failure in 50% of affected individuals. Most cases (>95%) are caused by genetic mutations in either the PKD1 or the PKD2 gene, or both, which encode polycystin-1 and polycystin-2, respectively. The present review provides a hint of how malfunction of polycystins may give rise to cysts, based on recent observations concerning polycystin channels. Polycystin channel signaling may prove to be an important new target for therapy of ADPKD.

Calcium Signaling↗