Skip to main content
SpringerLink
Log in

TRPML1: An Ion Channel in the Lysosome

  • Chapter
  • First Online:
Mammalian Transient Receptor Potential (TRP) Cation Channels

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 222))

Abstract

The first member of the mammalian mucolipin TRP channel subfamily (TRPML1) is a cation-permeable channel that is predominantly localized on the membranes of late endosomes and lysosomes (LELs) in all mammalian cell types. In response to the regulatory changes of LEL-specific phosphoinositides or other cellular cues, TRPML1 may mediate the release of Ca2+ and heavy metal Fe2+/Zn2+ions into the cytosol from the LEL lumen, which in turn may regulate membrane trafficking events (fission and fusion), signal transduction, and ionic homeostasis in LELs. Human mutations in TRPML1 result in type IV mucolipidosis (ML-IV), a childhood neurodegenerative lysosome storage disease. At the cellular level, loss-of-function mutations of mammalian TRPML1 or its C. elegans or Drosophila homolog gene results in lysosomal trafficking defects and lysosome storage. In this chapter, we summarize recent advances in our understandings of the cell biological and channel functions of TRPML1. Studies on TRPML1’s channel properties and its regulation by cellular activities may provide clues for developing new therapeutic strategies to delay neurodegeneration in ML-IV and other lysosome-related pediatric diseases.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abe K, Puertollano R (2011) Role of TRP channels in the regulation of the endosomal pathway. Physiology (Bethesda) 26:14–22

    Article  CAS  Google Scholar 

  • Bargal R, Avidan N, Ben-Asher E, Olender Z, Zeigler M, Frumkin A, Raas-Rothschild A, Glusman G, Lancet D, Bach G (2000) Identification of the gene causing mucolipidosis type IV. Nat Genet 26:118–123

    Article  CAS  PubMed  Google Scholar 

  • Bargal R, Avidan N, Olender T, Ben Asher E, Zeigler M, Raas-Rothschild A, Frumkin A, Ben-Yoseph O, Friedlender Y, Lancet D et al (2001) Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat 17:397–402

    Article  CAS  PubMed  Google Scholar 

  • Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G (2000) Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet 67:1110–1120

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Berman ER, Livni N, Shapira E, Merin S, Levij IS (1974) Congenital corneal clouding with abnormal systemic storage bodies: a new variant of mucolipidosis. J Pediatr 84:519–526

    Article  CAS  PubMed  Google Scholar 

  • Chen CS, Bach G, Pagano RE (1998) Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc Natl Acad Sci USA 95:6373–6378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cheng X, Shen D, Samie M, Xu H (2010) Mucolipins: intracellular TRPML1-3 channels. FEBS Lett 584:2013–2021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Curcio-Morelli C, Charles FA, Micsenyi MC, Cao Y, Venugopal B, Browning MF, Dobrenis K, Cotman SL, Walkley SU, Slaugenhaupt SA (2010) Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiol Dis 40:370–377

    Article  CAS  PubMed  Google Scholar 

  • Di Palma F, Belyantseva IA, Kim HJ, Vogt TF, Kachar B, Noben-Trauth K (2002) Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc Natl Acad Sci USA 99:14994–14999

    Article  PubMed Central  PubMed  Google Scholar 

  • Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–996

    Article  CAS  PubMed  Google Scholar 

  • Dong XP, Wang X, Shen D, Chen S, Liu M, Wang Y, Mills E, Cheng X, Delling M, Xu H (2009) Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. J Biol Chem 284:32040–32052

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M et al (2010a) PI(3,5)P(2) controls membrane traffic by direct activation of mucolipin Ca release channels in the endolysosome. Nat Commun 1:38

    Article  PubMed Central  PubMed  Google Scholar 

  • Dong XP, Wang X, Xu H (2010b) TRP channels of intracellular membranes. J Neurochem 113:313–328

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Eichelsdoerfer JL, Evans JA, Slaugenhaupt SA, Cuajungco MP (2010) Zinc dyshomeostasis is linked with the loss of mucolipidosis IV-associated TRPML1 ion channel. J Biol Chem 285:34304–34308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Falardeau JL, Kennedy JC, Acierno JS Jr, Sun M, Stahl S, Goldin E, Slaugenhaupt SA (2002) Cloning and characterization of the mouse Mcoln1 gene reveals an alternatively spliced transcript not seen in humans. BMC Genomics 3:3

    Article  PubMed Central  PubMed  Google Scholar 

  • Fares H, Greenwald I (2001) Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet 28:64–68

    CAS  PubMed  Google Scholar 

  • Galione A, Evans AM, Ma J, Parrington J, Arredouani A, Cheng X, Zhu MX (2009) The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels. Pflugers Arch 458:869–876

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grimm C, Jors S, Saldanha SA, Obukhov AG, Pan B, Oshima K, Cuajungco MP, Chase P, Hodder P, Heller S (2010) Small molecule activators of TRPML3. Chem Biol 17:135–148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grimm C, Hassan S, Wahl-Schott C, Biel M (2012) Role of TRPML and two-pore channels in endolysosomal cation homeostasis. J Pharmacol Exp Ther 342:236–244

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Soyombo AA, Tjon-Kon-Sang S, So I, Muallem S (2009) The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic 10:1157–1167

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kiselyov K, Chen J, Rbaibi Y, Oberdick D, Tjon-Kon-Sang S, Shcheynikov N, Muallem S, Soyombo A (2005) TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage. J Biol Chem 280:43218–43223

    Article  CAS  PubMed  Google Scholar 

  • Kukic I, Lee JK, Coblentz J, Kelleher SL, Kiselyov K (2013) Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. Biochem J 451:155–163

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • LaPlante JM, Falardeau J, Sun M, Kanazirska M, Brown EM, Slaugenhaupt SA, Vassilev PM (2002) 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 532:183–187

    Article  CAS  PubMed  Google Scholar 

  • LaPlante JM, Sun M, Falardeau J, Dai D, Brown EM, Slaugenhaupt SA, Vassilev PM (2006) Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol Genet Metab 89:339–348

    Article  CAS  PubMed  Google Scholar 

  • Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A (2012) Autophagy in lysosomal storage disorders. Autophagy 8:719–730

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Luzio JP, Bright NA, Pryor PR (2007a) The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Biochem Soc Trans 35:1088–1091

    Article  CAS  PubMed  Google Scholar 

  • Luzio JP, Pryor PR, Bright NA (2007b) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8:622–632

    Article  CAS  PubMed  Google Scholar 

  • Manzoni M, Monti E, Bresciani R, Bozzato A, Barlati S, Bassi MT, Borsani G (2004) Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization. FEBS Lett 567:219–224

    Article  CAS  PubMed  Google Scholar 

  • Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, Puri C, Pignata A, Martina JA, Sardiello M et al (2011) Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell 21:421–430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miedel MT, Weixel KM, Bruns JR, Traub LM, Weisz OA (2006) Posttranslational cleavage and adaptor protein complex-dependent trafficking of mucolipin-1. J Biol Chem 281:12751–12759

    Article  CAS  PubMed  Google Scholar 

  • Miedel MT, Rbaibi Y, Guerriero CJ, Colletti G, Weixel KM, Weisz OA, Kiselyov K (2008) Membrane traffic and turnover in TRP-ML1-deficient cells: a revised model for mucolipidosis type IV pathogenesis. J Exp Med 205:1477–1490

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morgan AJ, Platt FM, Lloyd-Evans E, Galione A (2011) Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem J 439:349–374

    Article  CAS  PubMed  Google Scholar 

  • Pryor PR, Reimann F, Gribble FM, Luzio JP (2006) Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic 7:1388–1398

    Article  CAS  PubMed  Google Scholar 

  • Puertollano R, Kiselyov K (2009) TRPMLs: in sickness and in health. Am J Physiol Renal Physiol 296:F1245–F1254

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Samie MA, Grimm C, Evans JA, Curcio-Morelli C, Heller S, Slaugenhaupt SA, Cuajungco MP (2009) The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1. Pflugers Arch 459(1):79–91

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shen D, Wang X, Xu H (2011) Pairing phosphoinositides with calcium ions in endolysosomal dynamics: phosphoinositides control the direction and specificity of membrane trafficking by regulating the activity of calcium channels in the endolysosomes. Bioessays 33:448–457

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shen D, Wang X, Li X, Zhang X, Yao Z, Dibble S, Dong XP, Yu T, Lieberman AP, Showalter HD et al (2012) Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun 3:731

    Article  PubMed Central  PubMed  Google Scholar 

  • Slaugenhaupt SA (2002) The molecular basis of mucolipidosis type IV. Curr Mol Med 2:445–450

    Article  CAS  PubMed  Google Scholar 

  • Slaugenhaupt SA, Acierno JS Jr, Helbling LA, Bove C, Goldin E, Bach G, Schiffmann R, Gusella JF (1999) Mapping of the mucolipidosis type IV gene to chromosome 19p and definition of founder haplotypes. Am J Hum Genet 65:773–778

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Spooner E, McLaughlin BM, Lepow T, Durns TA, Randall J, Upchurch C, Miller K, Campbell EM, Fares H (2013) Systematic screens for proteins that interact with the mucolipidosis type IV protein TRPML1. PLoS One 8:e56780

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS Jr, Bove C, Kaneski CR, Nagle J, Bromley MC et al (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9:2471–2478

    Article  CAS  PubMed  Google Scholar 

  • Thompson EG, Schaheen L, Dang H, Fares H (2007) Lysosomal trafficking functions of mucolipin-1 in murine macrophages. BMC Cell Biol 8:54

    Article  PubMed Central  PubMed  Google Scholar 

  • Venkatachalam K, Long AA, Elsaesser R, Nikolaeva D, Broadie K, Montell C (2008) Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135:838–851

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Venugopal B, Browning MF, Curcio-Morelli C, Varro A, Michaud N, Nanthakumar N, Walkley SU, Pickel J, Slaugenhaupt SA (2007) Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am J Hum Genet 81:1070–1083

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Venugopal B, Mesires NT, Kennedy JC, Curcio-Morelli C, Laplante JM, Dice JF, Slaugenhaupt SA (2009) Chaperone-mediated autophagy is defective in mucolipidosis type IV. J Cell Physiol 219:344–353

    Article  CAS  PubMed  Google Scholar 

  • Vergarajauregui S, Puertollano R (2006) Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes. Traffic 7:337–353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vergarajauregui S, Connelly PS, Daniels MP, Puertollano R (2008a) Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet 17:2723–2737

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vergarajauregui S, Oberdick R, Kiselyov K, Puertollano R (2008b) Mucolipin 1 channel activity is regulated by protein kinase A-mediated phosphorylation. Biochem J 410:417–425

    Article  CAS  PubMed  Google Scholar 

  • Vergarajauregui S, Martina JA, Puertollano R (2009) Identification of the penta-EF-hand protein ALG-2 as a Ca2 + -dependent interactor of mucolipin-1. J Biol Chem 284:36357–36366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vergarajauregui S, Martina JA, Puertollano R (2011) LAPTMs regulate lysosomal function and interact with mucolipin 1: new clues for understanding mucolipidosis type IV. J Cell Sci 124:459–468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J et al (2012) TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell 151:372–383

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu H, Delling M, Li L, Dong X, Clapham DE (2007) Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice. Proc Natl Acad Sci USA 104:18321–18326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamaguchi S, Jha A, Li Q, Soyombo AA, Dickinson GD, Churamani D, Brailoiu E, Patel S, Muallem S (2011) Transient receptor potential mucolipin 1 (TRPML1) and two-pore channels are functionally independent organellar ion channels. J Biol Chem 286:22934–22942

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zeevi DA, Frumkin A, Offen-Glasner V, Kogot-Levin A, Bach G (2009) A potentially dynamic lysosomal role for the endogenous TRPML proteins. J Pathol 219:153–162

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Li PL (2007) Reconstitution and characterization of a nicotinic acid adenine dinucleotide phosphate (NAADP)-sensitive Ca2+ release channel from liver lysosomes of rats. J Biol Chem 282:25259–25269

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Li X, Xu H (2012a) Phosphoinositide isoforms determine compartment-specific ion channel activity. Proc Natl Acad Sci USA 109:11384–11389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Y, McCartney AJ, Zolov SN, Ferguson CJ, Meisler MH, Sutton MA, Weisman LS (2012b) Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P(2) and PI(5)P. EMBO J 31(16):3442–3456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zolov SN, Bridges D, Zhang Y, Lee WW, Riehle E, Verma R, Lenk GM, Converso-Baran K, Weide T, Albin RL et al (2012) In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proc Natl Acad Sci USA 109:17472–17477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work in the author’s laboratory is supported by an NIH grants (NS062792, MH096595, and AR060837 to H.X). We appreciate the encouragement and helpful comments from other members of the Xu laboratory.

Author information

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI, 48109, USA

    Wuyang Wang, Xiaoli Zhang, Qiong Gao & Haoxing Xu

Authors
  1. Wuyang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haoxing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haoxing Xu .

Editor information

Editors and Affiliations

  1. Laboratory Ion Channel Research Campus Gasthuisberg, KU Leuven Department Cell Mol Medicin, Leuven, Belgium

    Bernd Nilius

  2. Institut für Experimentelle u. Klinische, Pharmakologie und Toxikologie, Universität des Saarlandes, Homburg, Saarland, Germany

    Veit Flockerzi

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Wang, W., Zhang, X., Gao, Q., Xu, H. (2014). TRPML1: An Ion Channel in the Lysosome. In: Nilius, B., Flockerzi, V. (eds) Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology, vol 222. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54215-2_24

Download citation

Publish with us

Policies and ethics

Search

Navigation