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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.37 no.4 Santiago  2004 


Biol Res 37: 681-691, 2004


The Gating of Polycystin Signaling Complex


Laboratoire de NeuroPhysiologie Cellulaire, CNRS-UMR 6150Faculté de Médecine, IFR Jean Roche, Bd. Pierre Dramard, 13916 Marseille Cedex 20, France.

Dirección para Correspondencia


Mutations in either polycystin-2 (PC2) or polycystin-1 (PC1) proteins cause severe, potentially lethal, kidney disorders (autosomal dominant polycystic kidney disease, ADPKD) and multiple extrarenal disease phenotypes. PC2, a member of the transient receptor potential channel superfamily and PC1, an orphan membrane receptor of largely unknown function, are thought to be part of a common signalling pathway. Here, I show that co-assembly of full-length PC1 with PC2 forms an ion channel signalling complex in which PC1 regulates PC2 channel gating through a structural rearrangement of the polycystin complex (Delmas et al., 2004a). These polycystin complexes function either as a receptor-cation channel or as a G-protein-coupled receptor. Thus, PC1 acts as a prototypical membrane receptor that regulates G-proteins and plasmalemmal PC2, a bimodal mechanism that may account for the multifunctional roles of polycystin proteins in various cell types. Genetic alteration of polycystin proteins such as those occurring in kidney diseases may impede polycystin signalling, thereby providing a likely mechanistic explanation to the pathogenesis of ADPKD. Our proposed mechanism may also be paradigmatic for the function of polycystin orthologues and other polycystin-related proteins in a variety of nonrenal cell types, including sperm, muscle cells and sensory neurons.

Key words: Polycystin, TRP channel, Sensory transduction, Calcium signaling, Polycystic Kidney Disease.


Polycystins form an expanding family of proteins composed of multiple members and orthologues in fish, invertebrates, mammals and humans that are widely expressed in various cell types and whose cellular functions remain poorly-defined (Stayner and Zhou, 2001). Recent advances, however, in human genetics of autosomal dominant polycystic kidney disease (ADPKD), an inherited disorder that is the most common cause of renal failure in man, has opened up new opportunities for a better understanding of polycystin functions. ADPKD is characterized by the progressive development of fluid-filled cysts in kidney and is accompanied by a number of extrarenal manifestations including hepatic and brain cysts, cardiac valvular abnormalities, cerebral and aortic aneurysms, colonic diverticulae and inguinal hernia (Gabow, 1990; Calvet and Grantham, 2001). Mutations in the PKD1 gene encoding polycystin-1 (PC1) account for the vast majority of patients with ADPKD, whereas mutations in the PKD2 gene encoding polycystin-2 (PC2) constitute a less prevalent genetic cause of ADPKD (Wu and Somlo, 2000). Despite intensive efforts aiming at delineating pathogenic ADPKD mechanisms, the nature of the aberrant gene products caused by mutations of PKD1 and PKD2 and the primary cellular events that initiate ADPKD are still obscure.

Consistent with the suggestion that polycystins play multifunctional roles in various tissues/organs throughout human embryogenesis and development, prominent expression of PKD1 and PKD2 genes is found in cardiomyocytes, endodermal derivatives, mesonephros and in neural tissues such as the anterior horn of the spinal cord and neural ganglia of 5- to 6-week human embryos (Chauvet et al., 2002). High levels of PKD1 persisted in mature derivatives of neural tube and neural crest in mouse (Guillaume et al., 1999) and nonepithelial cell types such as vascular smooth muscle, skeletal muscle, myocardiac cells and neurons in cerebral cortex, pons and medulla express both PC1 and PC2 proteins in human fetuses (Ong et al., 1999). An interesting discovery arising from mutation analysis in Caenorhabditis elegans indicates that lov-1, the homolog of PKD1, and pkd-2, the homolog of PKD2, are expressed in sensory neurons of male tails and participate in a single genetic pathway consistent with their involvement in chemo- and mechano-transduction (Barr and Sternberg, 1999). In a similar vein, recent evidence suggest that both proteins function in the same pathway and contribute to fluid-flow sensation by the primary cilium in renal epithelium (Nauli et al., 2003) and to cell cycle regulation and growth in mouse embryos (Bhunia et al., 2002). From these data and the conservation of polycystin pathways in multiple cell types, it can be hypothesized that polycystins act as sensors of the extracellular environment, initiating a variety of intracellular transduction signals in sensory and morphogenetic processes.

Although polycystin-1 and polycystin-2 are quite different in structure, with PC1 being ~4 times larger than PC2, both proteins show significant homology to each other in that the transmembrane region of PC2 shares ~50% sequence homology with the 6 transmembrane domains of PC1 (Sandford et al., 1997). PC1 is an integral membrane glycoprotein of about 4300 amino acids that is highly homologous to the sea urchin sperm receptor for egg jelly (suREJ1-3) proteins, which are responsible for triggering Ca2+ influx in the exocytotic acrosome reaction (Moy et al., 1996; Mengerink et al., 2002). It is composed of 11 transmembrane domains, a large N-terminal extracellular region containing a number of adhesive domains involved in protein-protein and protein-carbohydrate interactions and an intracellular C-terminal region of ~225 amino acids (Hughes et al., 1995; Sandford et al., 1997). PC1 is thought to act as an atypical, yet orphan, membrane receptor from its ability to activate G-proteins (Delmas et al., 2002a; Parnell et al., 2002) and c-Jun N-terminal kinase (Arnould et al., 1998) via its C-terminal business end. PC2, on the other hand, is a ~1000 amino acid protein with six putative transmembrane segments that forms a Ca2+-permeable, non-selective cation channel when functionally reconstituted in lipid bilayer or in oocyte expression systems (Hanaoka et al., 2000; González-Perrett et al., 2001; Vassilev et al., 2001). PC2 shares significant sequence homology to the a subunit of neuronal voltage-gated Ca2+ channels as well as to transient receptor potential channels (TrpC) (Mochizuki et al., 1996; Clapham, 2003; Delmas et al., 2004b). Its COOH terminus is thought to extend into the cytoplasm and contains a Ca2+-binding EF-hand and other distinct regions that can physically bind to PC1 and that are responsible for the interaction with TrpC1 and for the homodimerization of PC2 (Qian et al., 1997; Tsiokas et al., 1997; Lakkis and Zhou, 2003; Delmas, 2004). Because of its prominent location in the endoplasmic reticulum, PC2 has been suggested to function as a new type of intracellular Ca2+-release channel (Vassilev et al., 2001, Somlo and Ehrlich, 2001; Koulen et al., 2002) adding to the like of ryanodine and inositol triphosphate receptors.

The observation that mutations in either PKD1 or PKD2 genes produce virtually identical clinical symptoms (Wu and Somlo, 2000), irrespective of the causative gene, along with the finding that PC1 and PC2 may co-assemble in vivo (Newby et al., 2002), suggest that they function as constituents of a common signalling pathway or as interacting partners within a heteromeric polycystin complex. It is speculated that these polycystin complexes are part of a regulatory pathway involved in the control of membrane ion transport in target tissues that are defective in ADPKD. Nonetheless, progress in the functional characterization of these polycystin complexes has been slow and no clear-cut evidence has been provided so far to support their functional integrity. Indeed, our knowledge on the functional interaction between recombinant PC1 and PC2 is currently limited to the mutual regulation of their subcellular localization (Hanaoka et al, 2000; Grimm et al, 2003; Delmas et al., 2004a) and to the modulation of G-protein signalling of PC1 by PC2 (Delmas et al., 2002a). Further, although coordinate expression of PC1 and PC2 has been observed in many native tissues, the subcellular location of both proteins appears to be different with PC2 being an almost exclusive ER-located protein (Cai et al., 1999; Koulen et al, 2002) while PC1 is primarily found in the plasma membrane (Geng et al., 1996, Ong, 2000). Recent evidence, however, indicates that PC1 and PC2 are targeted to cilia membranes of renal epithelial cells, where the channel complex is gated by fluid flow (Nauli et al., 2003).

The characteristics and activation properties of polycystin complexes is discussed below with special emphasis on results recently obtained on heterologously expressed polycystin proteins (Delmas et al., 2002a, 2004a; Delmas, 2004). Several limitations have rendered studies of polycystin functions difficult, including the low levels of expression of endogenous PC1 in native cells and the low success rate of experiments directed at expression of recombinant full-length polycystins (Ong, 2000). These deficiencies have delayed the development of efficient model systems in which the functionality of polycystin complexes can be assessed. To overcome these limitations, we have over-expressed polycystin proteins in sympathetic neurons, a newly developed cell-expression system for assaying polycystin functions. This approach has clear advantages over more classical heterologous systems because sympathetic neurons can accommodate large size polycystin transcripts (over 14 kb) and provide a variety of well-characterized endogenous ion channels that can be used as cell signalling read-outs. Thus, we could monitor the expression and functional properties of recombinant polycystins, allowing us to study the structure/function relationships of polycystin complexes and their dynamic regulation in living cells.


Cultured sympathetic neurons from rat superior cervical ganglia (SCG) do not endogenously harbour PC1 and PC2 and can be manipulated using an intranuclear microinjection technique to accommodate high concentrations of CMV-driven eucaryot expression vectors. We have recently demonstrated that these cells constitute an excellent system for efficient expression of large PKD1 cDNA constructs (over 14 kb) and assaying polycystin-1 functions using endogenous ion channels as signaling read-outs (Delmas et al., 2002a,b). To reconstitute polycystin complexes, sympathetic neurons were intranuclearly microinjected with mPKD2 cDNA alone or in combination with hPKD1 cDNA. Confocal immunostaining performed 24-48 hr after gene delivery showed that mPC2 staining was mainly intracellular and restricted to the ER in cells microinjected with PKD2 cDNA alone. In contrast, mPC2 was found also concentrated in the plasma membrane when co-expressed with hPC1, in agreement with previous reports in CHO cells (Hanaoka et al., 2000). Co-expression of the C-terminal truncation mutant hPC1C193, which lacks the coiled-coil interaction domain with PC2, failed to bring PC2 to the cell surface although remaining itself targeted to the plasma membrane.

Whole-cell perforated patch-clamp recordings, made 48 hr after cDNA delivery showed that cells co-expressing mPC2 and hPC1 displayed a standing inward (cation) current with a mean amplitude of -2.15 ± 0.6 pA/pF. This current was absent in uninjected cells, mock cells (expressing GFP) or cells expressing hPC1 alone. The hPC1/mPC2 current had a reversal potential of -2 ± 3 mV and a relative permeability of Na+ to K+ to Ca2+ (calculated from GHK equation) of 1:0.98:0.57. It was suppressed by amiloride (IC50 42 ± 8 mM) and La3+ (IC50 62 ± 9 mM), two known blocking agents of PC2 channels (González-Perrett et al., 2001). The hPC1/mPC2 current was also suppressed by cytoplasmic microinjection of an antibody raised against an intracellular epitope (amino acids 44-62) located on the N-terminus of mPC2, indicating that mPC2 comprised the channel pore. Consistent with the lack of plasma membrane localization of mPC2 when expressed alone, only a tiny, if any, amiloride-sensitive inward current was seen in cells expressing mPC2.

Expression of the mPC2 mutant R742X lacking the C-terminal 226 amino acids, which includes the PC1 interaction domain and the ER retention signal, produced a significantly larger amiloride-sensitive inward current (-5.4 ± 0.5 pA/pF) than that obtained in hPC1/mPC2 expressing cells. The mPC2 R742X current had a similar reversal potential (-1 ± 2 mV) and pharmacology as the current generated by PC1/PC2 complexes.


Our data confirm and complement previous observations in other cell systems that PC1 is required for plasma membrane targeting of PC2 (cf. Hanaoka et al., 2000). But, in contrast to this previous report, we also show that PC1 is not necessary for PC2 to function as an ion channel. The larger current generated by PC2 R742X versus PC1/PC2 may further suggest that binding of PC1 to PC2 controls the gating of the channel, beside its plasmalemmal expression. To test this hypothesis, we made single channel recordings on somatic membranes of cells expressing either hPC1/mPC2 or mPC2 R742X channels, using Na+ as charge carrier. These recordings revealed inward (Na+) channel currents with main chord conductances of 90-130 pS in both cell types. Channel activities were suppressed by amiloride or La3+ added to the patch pipet and were not detected in mock cells or in cells expressing hPC1 alone.

The cation channels had a significantly higher po in mPC2 R742X cells than in hPC1/mPC2 cells (P < 0.001). For example, at -40 mV, the mPC2 R742X channel had a mean steady-state po of 0.37 that contrasted markedly with the low po of 0.11 of the hPC1/mPC2 channel complex. Both channel types showed a fairly voltage-independent po in the -20/-80 mV voltage range, consistent with the properties of their respective macroscopic currents. The overall properties of mPC2 channels described here are in good agreement with those of PC2 reconstituted in lipid bilayers (González-Perrett et al., 2001; 2002).


Our data support the idea that PC1 interaction with PC2 negatively regulates or stabilizes PC2 channel activity. This effect seems to be reciprocal since we have recently shown that PC2 reduces G-protein signalling by PC1 via mutual C-terminal interaction (Delmas et al., 2002a). To study the dynamic regulation of PC2 by PC1, we exploited the use of the polyclonal anti-hPC1 antibody MR3 as a putative ligand of hPC1. MR3 binds to amino-acids 2938-2956 on the N-terminal extracellular domain of hPC1 near the receptor for egg jelly (REJ) domain (Geng et al., 1996).

Local application of MR3 (diluted at 1/100 in Krebs solution) to cells co-expressing hPC1/mPC2 complexes induced a slowly-developing inward current (-8.6 ± 0.8 pA/pF) that was blocked by amiloride (Fig. 1). MR3 did not induce any currents when applied to mock cells or to cells expressing either hPC1 or mPC2. The MR3-induced current in hPC1/mPC2 cells was voltage-independent, reversed at -3 ± 2 mV and was suppressed by cytosolic microinjection of the mPC2 antibody, consistent with the involvement of PC2 subunits in this current. We confirmed the specificity of the anti-mPC2 antibody used in functional experiments by immunoprecipitating mPC2 subunits over-expressed in HEK293 cells. In addition, MR3 had no significant effect on membrane currents of cells co-expressing hPC1/mPC2 R742X or hPC1C193/mPC2, indicating that integrity of the C-terminal tails of both PC1 and PC2 is required for the functionality of the polycystin complex.

Figure 1. Polycystin ion channel currents activated by antibodies directed on extracellular domains of PC1. (A) Schematic representation of the structural organization of PC1 together with the extracellular binding sites of the anti-hPC1 (MR3/2938-2956) antibody used in functional experiments. LRR, leucin rich region; CLD, C-type lectin domain; PKD repeat, polycystin kidney disease repeat; REJ, receptor for egg jelly; TMS, transmembrane segment; C-c, coiled-coil domain. (B) Schematic illustration of the proposed membrane topology for hPC1 and mPC2. (C) Current-voltage relationships of cation currents evoked by MR3 antibody in a cell co-expressing hPC1 and mPC2. The I-V relationships were obtained by subtracting I-V curves in the presence or absence (control) of MR3 from those determined after adding amiloride (100 mM). Voltage-ramps were applied at 20 mV s-1.

Because we and other (e.g. Delmas et al., 2002a; Parnell et al., 2002) have shown that PC1 can constitutively activate Gi/o-type and/or Gq-type G-proteins, we examined the possibility that regulation of PC2 by antibody binding to PC1 can be secondary to G-protein activation. We first tested whether enhancement of PC2 activity was concordant with G-protein activation using endogenous N-type Ca2+ channels (ICa) as sensing molecules for activated G-proteins. In sympathetic neurons, N-type Ca2+ channels are inhibited by multiple G-protein-coupled receptors through G-protein bg subunits (Ikeda, 1996; Delmas et al., 2000). As evidenced by the strong voltage-dependent facilitation of Ca2+ currents observed following a conditioning voltage prepulse to +90 mV, a typical trademark of Gbg-mediated regulation of these channels, Ca2+ currents evoked in cells expressing hPC1 alone were found to be tonically inhibited by Gbg (Delmas et al., 2002a, 2004a). Application of MR3 had no significant effect on ICa in these cells or on ICa recorded in cells expressing mPC2 alone. As previously reported, tonic hPC1 modulation of Ca2+ currents was virtually absent in cells co-expressing mPC2, consistent with the presence of a physical competition between PC2 and Gi/o-proteins on the C-terminal domain of PC1 (see Delmas et al., 2002a). In striking contrast to hPC1-expressing cells, MR3 application onto hPC1/mPC2 cells produced a gradual inhibition of Ca2+ currents that presented all the characteristic features of Gbg modulation, i.e. slowing in the activation kinetics of ICa and relief of inhibition by large depolarizing voltages. MR3 no longer inhibits Ca2+ currents in the presence of G-transducin, a potent Gbg sequestering agent or following 24 hr pre-treatment with pertussis toxin (PTX), demonstrating that MR3 activates Gi/o-type G-proteins and releases their associated bg dimers.

Our data suggest that MR3 causes the rearrangement of PC1, which unmasks the PC1 G-protein binding site and leads to G-protein activation. Whether G-protein activation is responsible for PC2-enhanced activity was assessed in PTX-treated cells in which Gi/o-protein interaction with PC1 was prevented (see above). In such PTX-treated cells expressing hPC1/mPC2, MR3 application still evoked mPC2 currents that were blocked by amiloride and by intracellular microinjection of the anti-mPC2 antibody. Consistently, bath application of N-ethylmaleimide, another Gi/o-protein uncoupling agent, or intracellular dialysis of GDP-b-S, failed to prevent activation of PC2 currents by MR3 In addition, bath application of U73122 and intracellular dialysis of heparin, 8-NH2-cADPR or ruthenium red had no significant effect on the MR3-evoked PC2 current.

These data suggest that PC1 regulates PC2 channel gating by a mechanism that concomitantly activates G-proteins but that does not require either G-protein or PLC/Ca2+ signalling to occur.


Although progress in understanding the functions of PC2 has been relatively rapid, one major obstacle hampering investigation of PC1 and PC1/PC2 functions has been the lack of an efficient expression system for full-length recombinant PC1 (see Ong, 2000). Using sympathetic neurons as a novel expression system in which it was possible to deliver stochiometric concentrations of cDNA and to use endogenous ion channels as signalling real-time biosensors (Delmas et al., 2002a), we could study the functions of recombinant polycystin complexes and their dynamic regulations in living cells. Using this approach, we demonstrate that PC1 and PC2 form functionally-associated 'subunits' of a heteromultimeric receptor-ion channel signalling complex and that structural rearrangement of this complex dynamically regulates PC2 channel activity and triggers G-protein activation. To our knowledge, this coupling mechanism represents a new type of transduction device that may account for the multifunctional roles of polycystins in the regulation of cell differentiation, proliferation and ion transport.

PC1/PC2 complexes functionally reconstitute a novel surface Ca2+-permeant non-selective cation channel, in line with recent electrophysiological and biochemical findings (Hanaoka et al., 2000; Newby et al., 2002). Pharmacological and permeation properties of PC1/PC2 complex resemble those of recombinant homomeric PC2 or native PC2 from human term syncytiotrophoblasts reconstituted in lipid bilayers (González-Perrett et al., 2001, 2002). These include large single conductance, permeability to the cations K+, Na+ and Ca2+ and inhibition by La3+ and amiloride. These similarities, together with the observation that the anti-mPC2 antibody could block PC1/PC2 channel activity, strongly suggest that PC2 is the pore-forming subunit of the PC1/PC2 polycystin complex.

We extended these findings by showing that PC1 and PC2 form a complex in which the two polycystin proteins have mutual 'stabilizing/inhibitory' effects on each other function. Of relevance is the recent finding that a C-terminal fragment of murine PC1 seems to restore and stabilize PC2 activity following spontaneous inactivation in bilayer systems (Xu et al., 2003), reinforcing the idea that both proteins have strong functional interdependence.

Using application of antibodies against proximal N-terminal extracellular domains of PC1, we have demonstrated that PC1/PC2 complexes are dynamically regulated. Antibody binding to PC1 activated bi-directional signalling events, simultaneously enhancing PC2 gating and stimulating Gi/o-protein turnover. These effects appear to proceed through a structural rearrangement of the PC1/PC2 complex that requires integral C-termini of both proteins, since C-terminally truncated forms of PC1 and PC2 were unable to reconstitute a functional polycystin complex. Although we cannot exclude the possibility that regulation of PC2 by PC1 was mediated by a yet-unknown second messenger system, the findings that PC2 modulation is independent of G-protein and PLC signallings, in conjunction with the well-established physical interaction of PC1 and PC2, strongly support the idea that PC1/PC2 relationship occurs via conformational coupling. It is conceivable therefore that the concordant activation of PC2 and G-proteins results from the re-positioning of the respective carboxy terminal tails of PC1 and PC2, leading on one hand to the release of the G-protein binding site of PC1 and, on the other hand to conformational change of PC2 channel. At this juncture, the precise molecular stochiometry of the polycystin complex is uncertain. However, because of the propensity of PC2 to homodimerize rather than to heterodimerize with PC1 (Qian et al., 1997; Tsiokas et al., 1997), it is plausible that polycystin complex comprises an oligotetrameric PC2 channel bound to a single PC1 protein via C-terminal tethering. Collectively, our data suggest that binding of antibodies to the large extracellular domain of PC1 results in conformational change of the polycystin complex that ultimately leads to concordant activation of G-proteins and PC2, a mechanistic molecular sequence that fits well with the recently proposed role of PC1/PC2 complexes as mechano-fluid stress sensors in cilia embryonic kidney cells (Nauli et al., 2003). A simplified view of the proposed polycystin model is depicted in Figure 2.

Besides mechanical stimuli (cf Nauli et al., 2003), a challenging momentum remains to identify the putative ligands and molecular cues that activate the polycystin complexes and to define how these different factors adapt polycystin functions to the unique requirements of each tissue. PC1 is loaded with a number of adhesive motifs known to be involved in cell-cell or cell-matrix interactions that can be the receptacles for extracellular ligands. These include leucine-rich repeats, a C-type lectin domain, 16 immunoglobulin-like repeats (PKD domain), 4 type-III fibronectin-related domains, a REJ domain and a putative lipid-binding site (LH2/PLAT). Hitherto, the reported potential ligands comprise many focal adhesion proteins including talin, vinculin and paxillin and other proteins involved in cell-cell interaction such as E-cadherin, catenins and PC1 itself (Geng et al., 2000; Ibraghimov-Beskrovnaya et al., 2000). It will be of interest therefore to investigate whether heterotypic interactions of PC1 with other adhesion molecules, such as those of the cadherin family, or homophylic interactions of PC1 that play an important role in mediating intercellular adhesion can regulate polycystin signalling. In addition, because PC2 is also localized in the ER within cells (Gallagher et al., 2000; Koulen et al., 2002 and references therein), it remains to be tested whether PC1 can regulate PC2 in the store membrane.

Figure 2. Model for the activation of polycystin complex. Upper: PC1 and PC2 co-assemble in the plasma membrane via their COOH termini to form a stable polycystin complex that has little constitutive activity. Bottom: extracellular stimuli (antibody binding or flow) acting on the N-terminal extracellular domain of PC1 causes a structural rearrangement of the polycystin complex that unmasks the G-protein binding site located on the C-terminus of PC1 (grey boxes) and opens PC2. This leads to bi-directional signalling events via Gi/o G-proteins and intracellular calcium.



Our data show that PC1 co-assembles with PC2 to form a receptor-ion channel complex that regulates G-protein signalling and the activity of the polycystin channel functioning as a surface membrane Ca2+-permeable channel. Genetic alterations of PC1 and/or PC2 that are known to occur in ADPKD (Wu and Somlo, 2000) may interfere with the specific functions of these polycystin complexes and thus provide a possible mechanistic explanation of the pathophysiology of this disease. The biochemical detection of polycystin complexes in normal adult human kidney (Newby et al., 2002) further suggests that functional polycystin complexes are also required for the maintenance of renal structure and functions besides their roles during nephrogenesis (Wu et al., 1998; Nauli et al., 2003).

Our proposed mechanism may be paradigmatic for the function of other polycystin orthologs and related proteins in a variety of tissues. Ca2+-dependent signalling by PC1 is reminiscent of that occurring during the acrosome reaction, a prerequisite for sperm-egg fusion in sea urchin sperm. In these cells, it is the receptor for egg jelly, a membrane glycoprotein sharing domain homology with PC1, that binds to the egg jelly and triggers the acrosome reaction by increasing intracellular Ca2+ (Moy et al., 1996; Vacquier and Moy, 1997). In line with this, recent evidence indicate that the PC2 homolog in Drosophila is abundantly expressed in the tail and the acrosome-containing head region of sperm, in which it plays a key role in directional sperm movement and male fertility (Gao et al., 2003; Watnick et al., 2003). Previous data have also shown that the orthologs of PC1 and PC2 in C. elegans are expressed and concentrated in cilia and somatodendritic compartments of adult male sensory neurons and function in a common mechanosensory pathway during male mating behavior (Barr and Sternberg, 1999; Barr et al., 2001). Mechanistically, this may be similar to the role as mechano-fluid stress sensors of polycystin complexes in primary cilium of kidney cells (Nauli et al., 2003). PC2 is also required to establish left-right asymmetry in the mouse, where it is expressed in node monocilia and appears to sense nodal flow, initiating an asymmetric calcium signal at the left border of the node that may be responsible for expression of morphogenes (McGrath et al., 2003).

Thus, on the basis of developments reported here, it is conceivable that polycystins and related proteins function as mechano/chemo-transducers that generate calcium signals in response to various extracellular stimuli. Because polycystins are widely expressed and play multifunctional roles in the regulation of cell differentiation, proliferation and calcium transport, our data may be of primary relevance for understanding cyst formation in ADPKD as well as functions of the multiple members of the polycystin gene family in a variety of cells.


This work was supported by the Centre National de la Recherche Scientifique (CNRS) and by the Wellcome Trust. I would like to thank Dr. Jing Zhou (Brigham and Women's Hospital and Harvard Medical School, Boston, USA), Prof. David A. Brown (Dept. of Pharmacology, UCL, London, UK) and Dr. Marcel Crest (Intégration des Informations Sensorielles, CNRS-UMR 6150, Marseille, France) for support.


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Corresponding Author: Patrick Delmas, Laboratoire de NeuroPhysiologie Cellulaire, CNRS, UMR 6150, Faculté de Médecine, IFR Jean Roche, Bd. Pierre Dramard, 13916 Marseille Cedex 20, France. Tel: 00 33 4 91 69 89 70, Fax: 00 33 4 91 69 89 77, E-mail:

Received: January 14, 2004. Accepted: March 19, 2004.


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