Skip to main content

Advertisement

SpringerLink
Log in

Polycystins: polymodal receptor/ion-channel cellular sensors

  • Invited Review
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Transient receptor potential (TRP) channel proteins are divided into seven subgroups that are currently designated as TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPN (NOMP-C, from no mechanoreceptor potential-C), TRPA (ankyrin-like with transmembrane domains 1) and TRPP (polycystin). TRPC, TRPV and TRPM are related to canonical TRP proteins whereas TRPN, TRPA and TRPP (polycystin) are more divergent. Most TRP channels are linked to sensory stimuli, including phototransduction, thermosensation and mechanosensation. The TRPP subfamily was named after its founding member, polycystin kidney disease-2 (PKD2), a gene product mutated in many cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a major inherited nephropathy, affecting over 1:1,000 of the worldwide population, characterized by the progressive development of fluid-filled cysts from the tubules and collecting ducts of affected kidneys. Loss-of-function mutations in either polycystin-2, a non-selective cation channel, or polycystin-1 (PKD1), a large plasma membrane integral protein, give rise to ADPKD. PKD1 and PKD2 are thought to function together as part of a multiprotein receptor/ion-channel complex or independently and may be involved in transducing Ca2+-dependent mechanosensitive signals in response to cilia bending in renal epithelial cells and endodermally derived cells. Further information on the growing number and physiological properties of these TRP-polycystins is the basis of this review.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Alenghat FJ, Nauli SM, Kolb R, Zhou J, Ingber DE (2004) Global cytoskeletal control of mechanotransduction in kidney epithelial cells. Exp Cell Res 301:23–30

    Article  CAS  PubMed  Google Scholar 

  2. Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD (2003) Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39:497–511

    Article  CAS  PubMed  Google Scholar 

  3. Barr MM, DeModena J, Braun D, Nguyen CQ, Hall DH, Sternberg PW (2001) The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol 11:1341–1346

    Article  CAS  PubMed  Google Scholar 

  4. Barr MM, Sternberg PW (1999) A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401:386–389

    Article  CAS  PubMed  Google Scholar 

  5. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, Germino FJ, Germino GG (2002) PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109:157–168

    Article  CAS  PubMed  Google Scholar 

  6. Cai Y, Anyatonwu G, Okuhara D, Lee KB, Yu Z, Onoe T, Mei CL, Qian Q, Geng L, Witzgall R, Ehrlich BE, Somlo S (2004) Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812. J Biol Chem 279:19987–19995

    Article  CAS  PubMed  Google Scholar 

  7. Cai Y, Maeda Y, Cedzich A, Torres VE, Wu G, Hayashi T, Mochizuki T, Park JH, Wiztgall R, Somlo S (1999) Identification and characterization of polycystin-2, the PKD2 gene product. J Biol Chem 274:28557–28565

    Article  CAS  PubMed  Google Scholar 

  8. Calvet JP (2003) New insights into ciliary function: kidney cysts and photoreceptors. Proc Natl Acad Sci USA 100:5583–5585

    Article  CAS  PubMed  Google Scholar 

  9. Chen XZ, Segal Y, Basora N, Guo L, Peng JB, Babakhanlou H, Vassilev PM, Brown EM, Hediger MA, Zhou J (2001) Transport function of the naturally occurring pathogenic polycystin-2 mutant, R742X. Biochem Biophys Res Commun 282:1251–1256

    Article  CAS  PubMed  Google Scholar 

  10. Chen XZ, Vassilev PM, Basora N, Peng JB, Nomura H, Segal Y, Brown EM, Reeders ST, Hediger MA, Zhou J (1999) Polycystin-L is a calcium-regulated cation channel permeable to calcium ions. Nature 401:383–386

    Article  CAS  PubMed  Google Scholar 

  11. Corey DP (2003) New TRP channels in hearing and mechanosensation. Neuron 39:585–588

    Article  CAS  PubMed  Google Scholar 

  12. Corey DP, Garcia-Anoveros J, Holt JR, Kwan KY, Lin SY, Vollrath MA, Amalfitano A, Cheung EL, Derfler BH, Duggan A, Geleoc GS, Gray PA, Hoffman MP, Rehm HL, Tamasauskas D, Zhang DS (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432:723–730

    Article  CAS  PubMed  Google Scholar 

  13. Delmas P (2004) Assembly and gating of TRPC channels in signalling microdomains. Novartis Found Symp 258:75–102

    CAS  PubMed  Google Scholar 

  14. Delmas P (2004) Polycystins: from mechanosensation to gene regulation. Cell 118:145–148

    Article  CAS  PubMed  Google Scholar 

  15. Delmas P, Padilla F, Osorio N, Coste B, Raoux M, Crest M (2004) Polycystins, calcium signaling, and human diseases. Biochem Biophys Res Commun 322:1374–1383

    Article  CAS  PubMed  Google Scholar 

  16. Delmas P, Nauli SM, Li X, Coste B, Osorio N, Crest M, Brown DA, Zhou J (2004) Gating of the polycystin ion channel signaling complex in neurons and kidney cells. FASEB J 18:740–742

    CAS  PubMed  Google Scholar 

  17. Delmas P, Nomura H, Li X, Lakkis M, Luo Y, Segal Y, Fernandez-Fernandez JM, Harris P, Frischauf AM, Brown DA, Zhou J (2002) Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J Biol Chem 277:11276–11283

    Article  CAS  PubMed  Google Scholar 

  18. Foggensteiner L, Bevan AP, Thomas R, Coleman N, Boulter C, Bradley J, Ibraghimov-Beskrovnaya O, Klinger K, Sandford R (2000) Cellular and subcellular distribution of polycystin-2, the protein product of the PKD2 gene. J Am Soc Nephrol 11:814–827

    CAS  PubMed  Google Scholar 

  19. Gallagher AR, Cedzich A, Gretz N, Somlo S, Witzgall R (2000) The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proc Natl Acad Sci USA 97:4017–4022

    Article  CAS  PubMed  Google Scholar 

  20. Gao Z, Ruden DM, Lu X (2003) PKD2 cation channel is required for directional sperm movement and male fertility. Curr Biol 13:2175–2178

    Article  CAS  PubMed  Google Scholar 

  21. Gattone VH, Wang X, Harris PC, Torres VE (2003) Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 9:1323–1326

    Article  CAS  PubMed  Google Scholar 

  22. Gonzalez-Perrett S, Kim K, Ibarra C, Damiano AE, Zotta E, Batelli M, Harris PC, Reisin IL, Arnaout MA, Cantiello HF (2001) Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc Natl Acad Sci USA 98:1182–1187

    Article  CAS  PubMed  Google Scholar 

  23. Hamill OP, Martinac B (2001) Molecular basis of mechanotransduction in living cells. Physiol Rev 81:685–740

    CAS  PubMed  Google Scholar 

  24. Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG (2000) Co-assembly of polycystin-1 and −2 produces unique cation-permeable currents. Nature 408:990–994

    Article  CAS  PubMed  Google Scholar 

  25. Hang Le N et al (2004) Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signalling remains unaffected. J Biol Chem 26:27472–27481

    Google Scholar 

  26. Hirohashi S, Kanai Y (2003) Cell adhesion system and human cancer morphogenesis. Cancer Sci 94:575–581

    CAS  PubMed  Google Scholar 

  27. Hirohashi N, Vacquier VD (2002) High molecular mass egg fucose sulfate polymer is required for opening both Ca2+ channels involved in triggering the sea urchin sperm acrosome reaction. J Biol Chem 277:1182–1189

    Article  CAS  PubMed  Google Scholar 

  28. Huan Y, van Adelsberg J (1999) Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins. J Clin Invest 104:1459–1468

    CAS  PubMed  Google Scholar 

  29. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    Article  CAS  PubMed  Google Scholar 

  30. Kim E et al (1999) Interaction between RGS7 and polycystin. Proc Natl Acad Sci USA 96:6371–6376

    Article  CAS  PubMed  Google Scholar 

  31. Kim E, Arnould T, Sellin LK, Benzing T, Fan MJ, Gruning W, Sokol SY, Drummond I, Walz G (1999) The polycystic kidney disease 1 gene product modulates Wnt signalling. J Biol Chem 274:4947–4953

    Article  CAS  PubMed  Google Scholar 

  32. Köttgen M et al (2005) Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. EMBO J 24:705–716

    Article  PubMed  Google Scholar 

  33. Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S (2002) Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4:191–197

    Article  CAS  PubMed  Google Scholar 

  34. Li Q, Dai Y, Guo L, Liu Y, Hao C, Wu G, Basora N, Michalak M, Chen XZ (2003) Polycystin-2 associates with tropomyosin-1, an actin microfilament component. J Mol Biol 325:949–362

    Article  CAS  PubMed  Google Scholar 

  35. Li Q, Liu Y, Zhao W, Chen XZ (2002) The calcium-binding EF-hand in polycystin-L is not a domain for channel activation and ensuing inactivation. FEBS Lett 516:270–278

    CAS  PubMed  Google Scholar 

  36. Li A, Tian X, Sung SW, Somlo S (2003) Identification of two novel polycystic kidney disease-1-like genes in human and mouse genomes. Genomics 81:596–608

    Article  CAS  PubMed  Google Scholar 

  37. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–535

    Article  CAS  PubMed  Google Scholar 

  38. Luo Y, Vassilev PM, Li X, Kawanabe Y, Zhou J (2003) Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol Cell Biol 23:2600–2607

    Article  CAS  PubMed  Google Scholar 

  39. McGrath J, Somlo S, Makova S, Tian X, Brueckner M (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61–73

    Article  CAS  PubMed  Google Scholar 

  40. Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP (2005) TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat Cell Biol 7:179–185

    Article  CAS  PubMed  Google Scholar 

  41. Mengerink KJ, Moy GW, Vacquier VD (2000) suREJ proteins: new signalling molecules in sea urchin spermatozoa. Zygote 8:S28–S30

    PubMed  Google Scholar 

  42. Montell C et al (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231

    CAS  PubMed  Google Scholar 

  43. Moy GW, Mendoza LM, Schulz JR, Swanson WJ, Glabe CG, Vacquier VD (1996) The sea urchin sperm receptor for egg jelly is a modular protein with extensive homology to the human polycystic kidney disease protein, PKD1. J Cell Biol 133:809–817

    Article  CAS  PubMed  Google Scholar 

  44. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137

    Article  CAS  PubMed  Google Scholar 

  45. Neill AT, Moy GW, Vacquier VD (2004) Polycystin-2 associates with the polycystin-1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa. Mol Reprod Dev 67:472–477

    Article  CAS  PubMed  Google Scholar 

  46. Newby LJ, Streets AJ, Zhao Y, Harris PC, Ward CJ, Ong AC (2002) Identification, characterization, and localization of a novel kidney polycystin-1- polycystin-2 complex. J Biol Chem 277:20763–20773

    Article  CAS  PubMed  Google Scholar 

  47. Ong AC, Wheatley DN (2003) Polycystic kidney disease-the ciliary connection. Lancet 361:774–776

    Article  CAS  PubMed  Google Scholar 

  48. Parnell SC, Magenheimer BS, Maser RL, Rankin CA, Smine A, Okamoto T, Calvet JP (1998) The polycystic kidney disease-1 protein, polycystin-1, binds and activates heterotrimeric G-proteins in vitro. Biochem Biophys Res Commun 251:625–631

    Article  CAS  PubMed  Google Scholar 

  49. Parnell SC, Magenheimer BS, Maser RL, Zien CA, Frischauf AM, Calvet JP (2002) Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. J Biol Chem 277:19566–19572

    Article  CAS  PubMed  Google Scholar 

  50. Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, Witman GB (2002) Polycystin-2 localizes to the kidney cilia and the ciliary level is elevated in ORPK mice with polycystic kidney disease. Curr Biol 12:R378–R380

    Article  CAS  PubMed  Google Scholar 

  51. Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, Blum M, Dworniczak B (2002) The ion channel polycystin-2 is required for left–right axis determination in mice. Curr Biol 12:938–943

    Article  CAS  PubMed  Google Scholar 

  52. Praetorius HA, Frokiaer J, Leipziger J (2005) Transepithelial pressure pulses induce nucleotide release in polarized MDCK cells. Am J Physiol 288:F133–F141

    Google Scholar 

  53. Praetorius HA, Spring KR (2001) Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184:71–79

    Article  CAS  PubMed  Google Scholar 

  54. Praetorius HA, Spring KR (2003) Removal of the MDCK cell primary cilium abolishes flow sensing. J Membr Biol 191:69–76

    Article  CAS  PubMed  Google Scholar 

  55. Praetorius HA, Spring KR (2003) The renal cell primary cilium functions as a flow sensor. Curr Opin Nephrol Hypertens 12:517–520

    PubMed  Google Scholar 

  56. Puri S, Magenheimer BS, Maser RL, Ryan EM, Zien CA, Walker DD, Wallace DP, Hempson SJ, Calvet JP (2004) Polycystin-1 activates the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway. J Biol Chem 279:55455–55464

    Article  CAS  PubMed  Google Scholar 

  57. Qian F, Boletta A, Bhunia AK, Xu H, Liu L, Ahrabi AK, Watnick TJ, Zhou F, Germino GG (2002) Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proc Natl Acad Sci USA 99:16981–16986

    Article  CAS  PubMed  Google Scholar 

  58. Roitbak T, Ward CJ, Harris PC, Bacallao R, Ness SA, Wandinger-Ness A (2004) A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells. Mol Biol Cell 15:1334–1346

    Article  CAS  PubMed  Google Scholar 

  59. Scheffers MS, van der Bent P, Prins F, Spruit L, Breuning MH, Litvinov SV, de Heer E, Peters DJ (2000) Polycystin-1, the product of the polycystic kidney disease 1 gene, co-localizes with desmosomes in MDCK cells. Hum Mol Genet 9:2743–2750

    Article  CAS  PubMed  Google Scholar 

  60. Scheffers MS, van der Bent P, van de Wal A, van Eendenburg J, Breuning MH, de Heer E, Peters DJ (2004) Altered distribution and co-localization of polycystin-2 with polycystin-1 in MDCK cells after wounding stress. Exp Cell Res 292:219–230

    Article  CAS  PubMed  Google Scholar 

  61. Stacey M, Lin HH, Gordon S, McKnight AJ (2000). LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem Sci 25:284–289

    Article  CAS  PubMed  Google Scholar 

  62. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

    Article  CAS  PubMed  Google Scholar 

  63. Sutters M, Germino GG (2003) Autosomal dominant polycystic kidney disease: molecular genetics and pathophysiology. J Lab Clin Med 141:91–101

    Article  PubMed  Google Scholar 

  64. Sutters M, Yamaguchi T, Maser RL, Magenheimer BS, St John PL, Abrahamson DR, Grantham JJ (2001) Polycystin-1 transforms the cAMP growth-responsive phenotype of M-1 cells. Kidney Int 60:484–494

    Article  CAS  PubMed  Google Scholar 

  65. Syntichaki P, Tavernarakis N (2004) Genetic models of mechanotransduction: the nematode Caenorhabditis elegans. Physiol Rev 84:1097–1153

    Google Scholar 

  66. Torres VE, Harris PC (2003) Autosomal dominant polycystic kidney disease. Nefrologia 23:14–22

    PubMed  Google Scholar 

  67. Torres VE, Wang X, Qian Q, Somlo L, Harris PC, Gattone VH (2004) Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 10:363–364

    Article  CAS  PubMed  Google Scholar 

  68. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci USA 96:3934–3939

    Article  CAS  PubMed  Google Scholar 

  69. Vassilev PM, Guo L, Chen XZ, Segal Y, Peng JB, Basora N, Babakhanlou H, Cruger G, Kanazirska M, Ye C, Brown EM, Hediger MA, Zhou J (2001) Polycystin-2 is a novel cation channel implicated in defective intracellular Ca2+ homeostasis in polycystic kidney disease. Biochem Biophys Res Commun 282:341–350

    Article  CAS  PubMed  Google Scholar 

  70. Watnick TJ, Jin Y, Matunis E, Kernan MJ, Montell C (2003) A flagellar polycystin-2 homolog required for male fertility in Drosophila. Curr Biol 13:2179–2184

    Article  CAS  PubMed  Google Scholar 

  71. Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H Jr, Kucherlapati R, Edelmann W, Somlo S (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93:177–188

    Article  CAS  PubMed  Google Scholar 

  72. Wu G, Somlo S (2000) Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab 69:1–15

    Article  CAS  PubMed  Google Scholar 

  73. Xu GM, Gonzalez-Perrett S, Essafi M, Timpanaro GA, Montalbetti N, Arnaout MA, Cantiello HF (2003) Polycystin-1 activates and stabilizes the polycystin-2 channel. J Biol Chem 278:1457–1462

    Article  CAS  PubMed  Google Scholar 

  74. Xu GM, Sikaneta T, Sullivan BM, Zhang Q, Andreucci M, Stehle T, Drummond I, Arnaout MA (2001) Polycystin-1 interacts with intermediate filaments. J Biol Chem 276:46544–46552

    Article  CAS  PubMed  Google Scholar 

  75. Yamaguchi T et al (2003) Cyclic AMP activates B-raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994

    Article  CAS  PubMed  Google Scholar 

  76. Yamaguchi T, Wallace DP, Magenheimer BS, Hempson SJ, Grantham JJ, Calvet JP (2004) Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype. J Biol Chem 279:40419–40430

    Article  CAS  PubMed  Google Scholar 

  77. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508–2516

    Article  CAS  PubMed  Google Scholar 

  78. Yuasa T, Takakura A, Denker BM, Venugopal B, Zhou J (2004) Polycystin-1L2 is a novel G-protein-binding protein. Genomics 84:126–138

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by the Centre National de la Recherche Scientifique (CNRS).

Author information

Authors and Affiliations

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

    Patrick Delmas

Authors
  1. Patrick Delmas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Delmas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Delmas, P. Polycystins: polymodal receptor/ion-channel cellular sensors. Pflugers Arch - Eur J Physiol 451, 264–276 (2005). https://doi.org/10.1007/s00424-005-1431-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-005-1431-5

Keywords

Search

Navigation