Important insights in to the function of members of the TRP (transient receptor potential) channel superfamily have been gained from the identification of disease-related mutations. In particular the identification of mutations in the PKD2 gene in autosomal dominant polycystic kidney disease has revealed a link between TRP channel function, mechanosensation and the role of the primary cilium in renal cyst formation. The PKD2 gene encodes TRPP2 (transient receptor potential polycystin 2) that has significant homology to voltage-activated calcium and sodium TRP channels. It interacts with polycystin-1 to form a large membrane-associated complex that is localized to the renal primary cilium. Functional characterization of this polycystin complex reveals that it can respond to mechanical stimuli such as flow, resulting in influx of extracellular calcium and release of calcium from intracellular stores. TRPP2 is expressed in the endoplasmic reticulum/sarcoplasmic reticulum where it also regulates intracellular calcium signalling. Therefore TRPP2 modulates many cellular processes via intracellular calcium-dependent signalling pathways.

Introduction

TRP (transient receptor potential) channels form a superfamily of ubiquitously expressed heterotetrameric non-selective cation channels. Based on sequence and structural similarity, the TRP family can be divided into six classes, TRPA (TRP ankyrin), TRPC (TRP canonical), TRPM (TRP melastatin), TRPML (TRP mucolipin), TRPP (TRP polycystin) and TRPV (TRP vanilloid) [1]. More detailed descriptions about the TRP channel superfamily can be found in other papers in this issue of Biochemical Society Transactions. All TRP channels have a similar architecture with six TM (transmembrane) domains. Channel gating and selectivity is regulated by TM domains 5 and 6 and the intervening pore loop that faces the centre of the channel. In addition, each TRP channel family has its own unique set of domains and motifs in the N- or C-terminus.

TRP channels are ubiquitously expressed across evolution and have considerable functional diversity. They are principally associated with sensory transduction and the perception of a wide range of physical and chemical stimuli. These include responses to light, pain, touch, temperature, taste, osmolarity and pheromones [1]. However, their role now appears much broader than classical sensory transduction, as the functional characterization of novel TRP proteins has revealed many unexpected properties. Considerable functional data have been gained from the study of model organisms such as Caenorhabditis elegans and Drosophila. However, the clinical, molecular and cellular characterization of human diseases due to mutations in TRP channel genes has recently revealed exciting information on the function of individual TRP proteins and their role in normal physiology (Table 1). Nowhere has this been more elegantly demonstrated than from the study of ADPKD (autosomal dominant polycystic kidney disease) [2]. It is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and polycystin-2 (TRPP2) respectively. TRPP2 is the prototypic member of the TRPP class of TRP channels that includes TRPP3 and TRPP5 (Figure 1). TRPP2, TRPP3 and TRPP5 have also been called TRPP1, TRPP2 and TRPP3 respectively [3].

The domain architecture of the TRPP family of TRP channels

Figure 1
The domain architecture of the TRPP family of TRP channels

(A) Comparison of the domain architecture of members of the TRPP family. (B) Alignment of the C-terminal sequences of TRPP2 proteins showing the EF-hand (underlined in green), acid patch (underlined in yellow) and polycystin-1 interaction domains (underlined in red) (Pc1-ID). Ser812 is highlighted in green in the acid patch.

Figure 1
The domain architecture of the TRPP family of TRP channels

(A) Comparison of the domain architecture of members of the TRPP family. (B) Alignment of the C-terminal sequences of TRPP2 proteins showing the EF-hand (underlined in green), acid patch (underlined in yellow) and polycystin-1 interaction domains (underlined in red) (Pc1-ID). Ser812 is highlighted in green in the acid patch.

Table 1
TRP channels involved in human monogenic diseases

Data taken from Nilius et al. [53].

TRP channel Disease Inheritance Features OMIM 
TRPC6 Focal segmental glomerulosclerosis AD Proteinuria, renal failure 603965 
TRPM6 Hypomagnesaemia with secondary hypocalcemia AR Defective magnesium reabsorption 602014 
TRPP2 ADPKD AD Polycystic kidneys and liver 173900 
TRPML1 Mucolipidosis IV AR Neurodegenerative lysosomal storage disorder 252650 
TRP channel Disease Inheritance Features OMIM 
TRPC6 Focal segmental glomerulosclerosis AD Proteinuria, renal failure 603965 
TRPM6 Hypomagnesaemia with secondary hypocalcemia AR Defective magnesium reabsorption 602014 
TRPP2 ADPKD AD Polycystic kidneys and liver 173900 
TRPML1 Mucolipidosis IV AR Neurodegenerative lysosomal storage disorder 252650 

ADPKD

ADPKD is one of the commonest monogenic diseases of humans (OMIM 173900). It affects 1:1000 of the worldwide population and progresses to ESRF (end-stage renal failure) in most of the affected individuals. ADPKD is characterized by the progressive enlargement and destruction of the normal renal architecture by multiple fluid-filled cysts. It is a slowly progressive disease with ESRF usually developing in the sixth to eighth decades of life. Although 85% of cases are due to PKD1 mutations, disease associated with PKD1 or PKD2 mutations is clinically identical, suggesting that these two genes act in the same molecular pathway [4]. ADPKD is also commonly associated with cysts in the liver and cardiovascular complications such as hypertension and cerebral aneurysms [5].

TRPP2: structure and localization

TRPP2 is encoded by a 15 exon gene on chromosome 4 [6]. The 5.1 kb transcript contains a 2.9 kb open reading frame predicting a protein of 968 amino acids and molecular mass of 110 kDa. PKD2 is highly conserved across evolution, from yeast and C. elegans to humans. This property has been elegantly exploited to characterize the function of TRPP2 (see the next section). It is widely expressed during development and in adult tissues, suggesting that it has a conserved function essential for normal cellular physiology.

The predicted protein, TRPP2, has homology to the TRP superfamily and contains six TM domains and a pore loop between TM5 and TM6, with the N- and C-termini predicted to be intracellular (Figure 1) [6].

The C-terminal cytoplasmic region is 288 amino acids long. It contains several structural and functional domains. A single Ca2+-binding EF-hand domain (residues 754–782) is separated from a polycystin-1 interaction domain by a region that contains an acid cluster and an overlapping TRPP2 homodimerization domain (Figure 1) [7]. The helical polycystin-1 (Pc1-ID) interaction domain interacts with a coiled-coil domain in polycystin-1 [8]. No other domains are predicted in the N-terminal or loop regions of TRPP2.

TRPP2 has a dynamic expression pattern with localization documented in mitotic spindles, the ER/SR (sarcoplasmic reticulum), basolateral plasma membrane and more recently the primary cilium [912]. These locations in cultured cells and whole tissues are likely to reflect different roles of TRPP2 at different stages of cell differentiation and under different physiological conditions. However, it is the cilial localization that received most attention recently. This is largely because the primary cilium has been shown to play a central role in the control of left–right asymmetry and in renal cyst formation [13]. Most of the genes implicated in other diseases associated with polycystic kidney disease, including PKD1, encode proteins that localize to the basal body/cilial complex [14].

Experimental support for all the TRPP2 locations described above has been provided by the description of sequence motifs that either regulate subcellular localization or interact with sorting proteins. The C-terminus of TRPP2 contains an ER retention motif that when masked or deleted allows plasma membrane expression [9]. Sorting of TRPP2 is also regulated by several different proteins, including the phosphofurin acidic cluster sorting proteins PACS1/PACS2 and a novel protein PIGEA14 (polycystin-2 interactor, Golgi- and ER-associated 14) [15,16]. PACS1 and PACS2 bind to an acidic cluster in a C-terminal region that overlaps with the ER retention motif. Binding is dependent on phosphorylation of Ser812 by protein kinase CK2. Loss of binding either by mutagenesis or by protein kinase CK2 inhibition results in plasma membrane localization. PIGEA14, however, is required for ER-to-Golgi trafficking. An N-terminal phosphoserine, Ser76, has also been implicated in sorting to the plasma membrane [17]. Cilial localization, however, is regulated by different mechanisms and is independent of Ser812, Ser76 and polycystin-1. An N-terminal RVXP motif directs cilial localization, which is also dependent on IFT20 (intraflagellar transport 20), a highly conserved IFT protein that directs Golgi-to-cilia trafficking [18,19].

TRPP3 differs from TRPP2 in the organization of its C-terminus. It lacks the acidic cluster but has the EF-hand domain and the polycystin-1-interacting domain. This offers an explanation for the observation that TRPP3 is localized to the plasma membrane and interacts with polycystin-1 [20,21].

TRPP2-interacting proteins

In addition to PACS1 and PACS2 that are involved in trafficking, TRPP2 interacts with a diverse range of other proteins.

The best-characterized functional interaction of TRPP2 is with polycystin-1 via their C-terminal domains to form a cell surface ion channel or signalling complex [8]. Both proteins may also function independently, as demonstrated by the lack of expression of polycystin-1 in nodal cilia that control left–right asymmetry in a TRPP2-dependent manner [22]. The polycystin complex has been shown to regulate several different signalling pathways including JAK (Janus kinase)/STAT (signal transducer and activator of transcription)- and Id2-regulated transcription [23,24]. Each appears to have an effect on regulating the cell cycle and cell proliferation. Defects in cell proliferation have been described in ADPKD cystic epithelia and antiproliferative agents have also been shown to be of therapeutic benefit in animal models of PKD (polycystic kidney disease) [25]. It is not known whether most TRPP2 functions are dependent on the interaction with polycystin-1.

Interactions with Hax1, α-actinin and CD2-AP (CD2-associated protein) all suggest that TRPP2 regulates or is regulated by the actin cytoskeleton [2628]. This is supported by loss of physical-stress-induced TRPP2 activity in the presence of the actin cytoskeleton disrupter cytochalasin D [29]. The functional implications of a TRPP2 interaction with another TRP channel, TRPC1, remain unknown, but the recent identification of TRPC1 as a stretch-activated cation channel further supports the hypothesis that TRPP2 forms part of a mechanosensitive channel complex [30,31]. The recently described interaction of TRPP2 with IP3R (inositol trisphosphate receptor) suggests a central role of TRPP2 in regulating intracellular Ca2+ concentrations [32].

Model organisms and TRPP2 function

TRPP2 is highly conserved across evolution. Therefore many model organisms have been used to study its function (Table 2). In yeast, pkd2 is involved in cell growth, cell shape and cell wall synthesis via interaction with Rho1 GTPase [33]. The identification of defective male mating behaviour in C. elegans provided the first clues to its wider physiological role [34]. The C. elegans homologue of TRPP2 is expressed in the cilia of sensory neurones and implicated in vulva location and chemotaxis. It also interacts in the same pathway as the C. elegans homologue of PKD1, lov1. In sea urchin, TRPP2 is critical to the Ca2+-dependent sperm acrosome reaction, being activated by polycystin-1 orthologues containing the REJ (receptor for egg jelly) domain [35]. In Drosophila, which only has two ciliated cell types, sensory neurons and sperm, Pkd2 mutants have defects in sperm motility, fertility and smooth-muscle function [36,37]. This suggested a further, non-ciliary role for TRPP2 in regulating muscle contraction through intracellular Ca2+ homoeostasis.

Table 2
Model organisms and TRPP2 function
Organism Function Reference 
Yeast Cell wall synthesis [33
C. elegans Male mating behaviour [34
Sea urchin Acrosome reaction [35
Zebrafish L–R (left–right) asymmetry, renal tubulogenesis [38,39
Mouse L–R asymmetry, cardiac, pancreatic and renal development [40,41
Organism Function Reference 
Yeast Cell wall synthesis [33
C. elegans Male mating behaviour [34
Sea urchin Acrosome reaction [35
Zebrafish L–R (left–right) asymmetry, renal tubulogenesis [38,39
Mouse L–R asymmetry, cardiac, pancreatic and renal development [40,41

In zebrafish, knockdown of TRPP2 expression results in abnormalities of laterality, with defective heart and gut looping and the development of pronephric cysts [38,39]. Both defects have been linked to defects in cilial function. In mouse, similar defects are also seen with Pkd2-null animals having laterality defects and PKD [40]. Cardiac septation defects and pancreatic cysts also occur, features all seen in Pkd1 mutant mice [41]. When Pkd2 heterozygous mice are induced to develop hypertension, they develop intracranial vascular malformations consistent with a role for TRPP2 in vascular smooth-muscle cells [42]. Indeed, isolated vascular smooth-muscle cells have significantly altered intracellular Ca2+ homoeostasis, with a reduction in resting intracellular Ca2+ and total SR Ca2+ concentrations [42]. SOC (store-operated Ca2+) channel activity is also decreased, indicating that heterozygosity for a single Pkd2 mutation is sufficient to alter intracellular Ca2+ homoeostasis.

TRPP2 functions as a Ca2+-permeable cation channel

The first evidence that members of the TRPP family function as cation channels came with the demonstration in 1999 that PKDL (PKD-like) (TRPP3 or PKD2L1) was a calcium-regulated cation channel permeable to calcium ions [21]. Subsequently, TRPP2 channel activity has been demonstrated in a variety of different cell and cell-free systems (reviewed in [43]). The interaction with polycystin-1 is important for the formation of plasma membrane channels. The interaction facilitates the translocation of TRPP2 to the plasma membrane and is required for channel activity [44]. Polycystin-1 alone cannot form an ion channel but does function as a G-protein-coupled receptor [45]. However, polycystin-1 and polycystin-2 are now known to traffic independently to the cilium, so different mechanisms of channel assembly, trafficking and regulation appear to be important in different locations. In this complex, activity of the TRPP2 channel can be regulated by polycystin-1, while TRPP2 can also regulate the signalling function of polycystin-1. The extracellular region of polycystin-1 appears to be important for channel regulation as antibodies to the REJ domain can activate TRPP2 and G-proteins [46]. Polycystin-1 signalling functions modulated by TRPP2 include JAK/STAT activation as well as AP-1 (activating protein 1) activation due to nuclear translocation of the C-terminus of polycystin-1 [23,47].

Therefore considerable evidence exists to support an ion channel and signalling function for the polycystin complex. However, TRPP2 can also form functional channels in the absence of polycystin-1. In isolated ER membranes, TRPP2 functions as a calcium channel, suggesting that it may act as an ER calcium release channel in vivo, a hypothesis that now has experimental support [48]. The activation of TRPP2 by Ca2+ identified TRPP2 as being involved in Ca2+-induced Ca2+ release. It demonstrates a bell-shaped response curve to Ca2+ that is dependent on the C-terminus of the protein as this property is lost in channels with the L703X mutation that truncates TRPP2 just after the last TM. The role of the Ca2+-binding EF-hand domain in this process is unknown, although in TRPP3 the EF-hand domain is not required for Ca2+ regulation. Intriguingly Ser812 is required for Ca2+ regulation [49].

Therefore TRPP2 can function as a Ca2+ channel in the plasma membrane and ER/SR. Apart from Ca2+ itself and polycystin-1, other stimuli that activate channel activity are unknown. Recently, EGF (epidermal growth factor) has been shown to activate TRPP2 but it is the mechanosensitive properties of the channel and of the polycystin complex that have attracted considerable recent attention [50].

The polycystin-1–TRPP2 protein complex: a mechanosensitive ion channel

The presence of TRPP2 channels at points of cell–cell contact and in the cilial membrane suggests that it may directly respond to mechanical stimuli such as alterations in cell shape and fluid flow. In this model, polycystin-1 may function as a mechanical sensor regulating TRPP2 activity. Support for this has come from a number of studies. The renal primary cilium has been shown to be capable of transducing direct or flow-induced deflection into an increase in intracellular Ca2+ concentration [51]. In renal tubular epithelial cells derived from Pkd1−/− mice, this response to flow is abolished, suggesting that polycystin-1 forms part of the flow-sensing pathway. The response is also abolished with antibodies directed against TRPP2 and the extracellular PKD domains of polycystin-1. The 16 PKD domains of polycystin-1 which form nearly 50% of the extracellular part of polycystin-1, have been shown to have unique physical properties [52]. Under tension they are able to form highly stable intermediate structures that are able to withstand considerable force – a likely requirement of a mechanosensor. However, the cilial response to flow is not always dependent on polycystin-1. As has already been stated, polycystin-1 is not expressed in nodal cilia, which detect flow and regulate laterality in a TRPP2-dependent manner – further evidence that TRPP2 may be directly activated by mechanical stimuli.

Conclusion

The identification of the molecular defect in ADPKD as a defect in a TRP channel, TRPP2, has led to exciting new hypotheses and experimental data on the mechanisms of TRP channel activation and regulation. TRPP2 has a variety of physiological roles including regulating smooth-muscle and cilial function, processes that are critically regulated by intracellular calcium concentration. TRPP2 functions as a Ca2+-induced Ca2+ release channel in the ER/SR and as a mechanosensitive calcium entry channel in the cilial plasma membrane. The precise mechanism of its activation remains to be fully elucidated but its link to EGF, the actin cytoskeleton, the IP3R and polycystin-1 suggests that many mechanisms may operate including chemical and physical stimuli. While further delineating the wide array of physiological functions of TRP channels, the study of TRPP2 may also open new therapeutic opportunities in ADPKD.

Cell and Molecular Biology of TRP Channels: Biochemical Society Focused Meeting held at University of Bath, U.K., 7–8 September 2006. Organized and Edited by D. Beech (Leeds, U.K.), B. Reaves (Bath, U.K.) and A. Wolstenholme (Bath, U.K.).

Abbreviations

     
  • ADPKD

    autosomal dominant polycystic kidney disease

  •  
  • EGF

    epidermal growth factor

  •  
  • ER

    endoplasmic reticulum

  •  
  • ESRF

    end-stage renal failure

  •  
  • IFT

    intraflagellar transport

  •  
  • IP3R

    inositol trisphosphate receptor

  •  
  • JAK

    Janus kinase

  •  
  • PACS

    phosphofurin acidic cluster sorting protein

  •  
  • PIGEA14

    polycystin-2 interactor, Golgi- and ER-associated 14

  •  
  • PKD

    polycystic kidney disease

  •  
  • REJ

    receptor for egg jelly

  •  
  • SR

    sarcoplasmic reticulum

  •  
  • STAT

    signal transducer and activator of transcription

  •  
  • TM

    transmembrane

  •  
  • TRP

    transient receptor potential

  •  
  • TRPC

    TRP canonical

  •  
  • TRPM

    TRP melastatin

  •  
  • TRPP

    TRP polycystin

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