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PMID: 15971078 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

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

Pflugers Archiv : European journal of physiology ·Vol. 451 ·No. 1 ·2005-10-00 ·Pages 277-85

Qian F, Noben-Trauth K

Abstract

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.

MeSH Terms
Animals Calcium Channels Disease Models, Animal Humans Membrane Glycoproteins/physiology Membrane Proteins Mucolipidoses/physiopathology Polycystic Kidney, Autosomal Dominant/physiopathology TRPM Cation Channels/physiology TRPP Cation Channels Transient Receptor Potential Channels/physiology
Chemicals
Calcium Channels MCOLN1 protein, human MCOLN3 protein, human Mcoln2 protein, human Membrane Glycoproteins Membrane Proteins PKD2L2 protein, human TRPM Cation Channels TRPP Cation Channels Transient Receptor Potential Channels polycystic kidney disease 2 protein
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Qian Feng
Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. fqjhupkd@jhmi.edu
Noben-Trauth Konrad
References (71)
71 references, click to expand
  1. suREJ3, a polycystin-1 protein, is cleaved at the GPS domain and localizes to the acrosomal region of sea urchin sperm.
    J Biol Chem. 2002 Jan 11;277(2):943-8 PMID: 11696547
  2. Identification of a human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like protein.
    Hum Mol Genet. 1999 Mar;8(3):543-9 PMID: 9949214
  3. Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease.
    Biochem Biophys Res Commun. 2001 Mar 23;282(1):341-50 PMID: 11264013
  4. The neurogenetics of mucolipidosis type IV.
    Neurology. 2002 Aug 13;59(3):306-13 PMID: 12182165
  5. The KLP-6 kinesin is required for male mating behaviors and polycystin localization in Caenorhabditis elegans.
    Curr Biol. 2005 Mar 8;15(5):394-404 PMID: 15753033
  6. Cellular and subcellular distribution of polycystin-2, the protein product of the PKD2 gene.
    J Am Soc Nephrol. 2000 May;11(5):814-27 PMID: 10770959
  7. Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway.
    FEBS Lett. 2002 Dec 4;532(1-2):183-7 PMID: 12459486
  8. Family ties of gated pores: evolution of the sensor module.
    FASEB J. 2002 Oct;16(12):1623-9 PMID: 12374785
  9. 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. 2002 Apr 19;109 (2):157-68 PMID: 12007403
  10. Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease.
    Curr Biol. 2002 Jun 4;12(11):R378-80 PMID: 12062067
  11. TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells.
    Nature. 2004 Dec 9;432(7018):723-30 PMID: 15483558
  12. Mucolipidosis IV, a sialolipidosis due to ganglioside sialidase deficiency.
    J Inherit Metab Dis. 1982;5(4):218-24 PMID: 6820444
  13. Abnormal ganglioside accumulation in cultured fibroblasts from patients with mucolipidosis IV.
    Biochem Biophys Res Commun. 1975 Oct 27;66(4):1483-90 PMID: 1191304
  14. Transport function of the naturally occurring pathogenic polycystin-2 mutant, R742X.
    Biochem Biophys Res Commun. 2001 Apr 20;282(5):1251-6 PMID: 11302751
  15. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium.
    Cell. 1994 Aug 26;78(4):725 PMID: 8069919
  16. A flagellar polycystin-2 homolog required for male fertility in Drosophila.
    Curr Biol. 2003 Dec 16;13(24):2179-84 PMID: 14680634
  17. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2.
    J Biol Chem. 2002 Mar 29;277(13):11276-83 PMID: 11786542
  18. Polycystin-2 associates with the polycystin-1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa.
    Mol Reprod Dev. 2004 Apr;67(4):472-7 PMID: 14991739
  19. PKD1 interacts with PKD2 through a probable coiled-coil domain.
    Nat Genet. 1997 Jun;16(2):179-83 PMID: 9171830
  20. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.
    Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6965-70 PMID: 9192675
  21. Identification of the gene causing mucolipidosis type IV.
    Nat Genet. 2000 Sep;26(1):118-23 PMID: 10973263
  22. Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia.
    Mol Cell Biol. 2003 Apr;23(7):2600-7 PMID: 12640140
  23. Genomic organization and functional analysis of murine PKD2L1.
    J Biol Chem. 2005 Feb 18;280(7):5626-35 PMID: 15548533
  24. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.
    J Am Soc Nephrol. 2002 Oct;13(10):2508-16 PMID: 12239239
  25. The cell biology of lysosomal storage disorders.
    Nat Rev Mol Cell Biol. 2004 Jul;5(7):554-65 PMID: 15232573
  26. Polycystins: what polycystic kidney disease tells us about sperm.
    Mol Reprod Dev. 2004 Apr;67(4):385-8 PMID: 14991728
  27. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.
    Nat Genet. 2003 Feb;33(2):129-37 PMID: 12514735
  28. Identification and characterization of polycystin-2, the PKD2 gene product.
    J Biol Chem. 1999 Oct 1;274(40):28557-65 PMID: 10497221
  29. Mutations in Mlph, encoding a member of the Rab effector family, cause the melanosome transport defects observed in leaden mice.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98 (18):10238-43 PMID: 11504925
  30. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.
    Nat Genet. 1995 Jun;10(2):151-60 PMID: 7663510
  31. Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog.
    Nat Genet. 2001 May;28(1):64-8 PMID: 11326278
  32. Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812.
    J Biol Chem. 2004 May 7;279(19):19987-95 PMID: 14742446
  33. Mutation of melanosome protein RAB38 in chocolate mice.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4471-6 PMID: 11917121
  34. Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development.
    Am J Pathol. 2002 Mar;160(3):973-83 PMID: 11891195
  35. PKD2 cation channel is required for directional sperm movement and male fertility.
    Curr Biol. 2003 Dec 16;13(24):2175-8 PMID: 14680633
  36. The ion channel polycystin-2 is required for left-right axis determination in mice.
    Curr Biol. 2002 Jun 4;12(11):938-43 PMID: 12062060
  37. Distinct subcellular expression of endogenous polycystin-2 in the plasma membrane and Golgi apparatus of MDCK cells.
    Hum Mol Genet. 2002 Jan 1;11(1):59-67 PMID: 11772999
  38. The calcium-binding EF-hand in polycystin-L is not a domain for channel activation and ensuing inactivation.
    FEBS Lett. 2002 Apr 10;516(1-3):270-8 PMID: 11959145
  39. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis.
    Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4483-8 PMID: 15070744
  40. 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 U S A. 2002 Dec 24;99(26):16981-6 PMID: 12482949
  41. Identification of an organelle receptor for myosin-Va.
    Nat Cell Biol. 2002 Apr;4(4):271-8 PMID: 11887186
  42. Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2).
    Eur J Hum Genet. 1999 Dec;7(8):860-72 PMID: 10602361
  43. Phospholipids accumulation in mucolipidosis IV cultured fibroblasts.
    J Inherit Metab Dis. 1988;11(2):144-50 PMID: 3139925
  44. Identification of two novel polycystic kidney disease-1-like genes in human and mouse genomes.
    Genomics. 2003 Jun;81(6):596-608 PMID: 12782129
  45. Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV.
    Biochem Biophys Res Commun. 2004 Oct 1;322(4):1384-91 PMID: 15336987
  46. The TRP superfamily of cation channels.
    Sci STKE. 2005 Feb 22;2005(272):re3 PMID: 15728426
  47. The sequence, expression, and chromosomal localization of a novel polycystic kidney disease 1-like gene, PKD1L1, in human.
    Genomics. 2002 Mar;79(3):376-86 PMID: 11863367
  48. Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel.
    Hum Mol Genet. 2004 Mar 15;13(6):617-27 PMID: 14749347
  49. ATP-2 interacts with the PLAT domain of LOV-1 and is involved in Caenorhabditis elegans polycystin signaling.
    Mol Biol Cell. 2005 Feb;16(2):458-69 PMID: 15563610
  50. Specific association of the gene product of PKD2 with the TRPC1 channel.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3934-9 PMID: 10097141
  51. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.
    Science. 1996 May 31;272(5266):1339-42 PMID: 8650545
  52. Mucopolysaccharide accumulation in cultured skin fibroblasts derived from patients with mucolipidosis IV.
    Am J Hum Genet. 1977 Nov;29(6):610-8 PMID: 145180
  53. PIGEA-14, a novel coiled-coil protein affecting the intracellular distribution of polycystin-2.
    J Biol Chem. 2004 Aug 13;279(33):35009-16 PMID: 15194699
  54. Polycystin-L is a calcium-regulated cation channel permeable to calcium ions.
    Nature. 1999 Sep 23;401(6751):383-6 PMID: 10517637
  55. The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4355-60 PMID: 11904372
  56. The molecular basis of mucolipidosis type IV.
    Curr Mol Med. 2002 Aug;2(5):445-50 PMID: 12125810
  57. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel.
    Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1182-7 PMID: 11252306
  58. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.
    Hum Mol Genet. 2000 Oct 12;9(17):2471-8 PMID: 11030752
  59. Two populations of node monocilia initiate left-right asymmetry in the mouse.
    Cell. 2003 Jul 11;114(1):61-73 PMID: 12859898
  60. Polycystin-2 is an intracellular calcium release channel.
    Nat Cell Biol. 2002 Mar;4(3):191-7 PMID: 11854751
  61. Combined cochleo-saccular and neuroepithelial abnormalities in the Varitint-waddler-J (VaJ) mouse.
    Hear Res. 1998 Sep;123(1-2):125-36 PMID: 9745961
  62. Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity.
    J Biol Chem. 2002 Jul 12;277(28):24959-66 PMID: 11991947
  63. Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation.
    EMBO J. 2005 Feb 23;24(4):705-16 PMID: 15692563
  64. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans.
    Nature. 1999 Sep 23;401(6751):386-9 PMID: 10517638
  65. Mucolipidosis type IV.
    Mol Genet Metab. 2001 Jul;73(3):197-203 PMID: 11461186
  66. Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice.
    Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14994-9 PMID: 12403827
  67. Infertility in adults with polycystic kidney disease.
    Nephrol Dial Transplant. 2003 Jan;18(1):190-1 PMID: 12480981
  68. 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. 1996 May;133(4):809-17 PMID: 8666666
  69. Evolutionary conservation of Drosophila polycystin-2 as a calcium-activated cation channel.
    J Am Soc Nephrol. 2004 May;15(5):1168-77 PMID: 15100357
  70. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway.
    Curr Biol. 2001 Sep 4;11(17):1341-6 PMID: 11553327
  71. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents.
    Nature. 2000 Dec 21-28;408(6815):990-4 PMID: 11140688
Article Info
Journal
Pflugers Archiv : European journal of physiology
Abbr.
Pflugers Arch
ISSN
0031-6768
DOI
10.1007/s00424-005-1469-4
Email
fqjhupkd@jhmi.edu
Published
2005-10-00
Epub
2005-00-22
Pages
277-85
Language
English
Region
Germany
NLM ID
0154720
Subset
IM
Grants
NIDDK NIH HHS · R01 DK062199 · United States
External Links
PubMed source DOI: 10.1007/s00424-005-1469-4 View journal details
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