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Research ArticlePerspectives in Pharmacology

Role of TRPML and Two-Pore Channels in Endolysosomal Cation Homeostasis

Christian Grimm, Sami Hassan, Christian Wahl-Schott and Martin Biel
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 236-244; DOI: https://doi.org/10.1124/jpet.112.192880
Christian Grimm
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Sami Hassan
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Christian Wahl-Schott
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Martin Biel
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Abstract

The transient receptor potential (TRP) channels TRPML1, TRPML2, and TRPML3 (also called mucolipins 1–3 or MCOLN1–3) are nonselective cation channels. Mutations in the Trpml1 gene cause mucolipidosis type IV in humans with clinical features including psychomotor retardation, corneal clouding, and retinal degeneration, whereas mutations in the Trpml3 gene cause deafness, circling behavior, and coat color dilution in mice. No disease-causing mutations are reported for the Trpml2 gene. Like TRPML channels, which are expressed in the endolysosomal pathway, two-pore channels (TPCs), namely TPC1, TPC2, and TPC3, are found in intracellular organelles, in particular in endosomes and lysosomes. Both TRPML channels and TPCs may function as calcium/cation release channels in endosomes, lysosomes, and lysosome-related organelles with TRPMLs being activated by phosphatidylinositol 3,5-bisphosphate and regulated by pH and TPCs being activated by nicotinic acid adenine dinucleotide phosphate in a calcium- and pH-dependent manner. They may also be involved in endolysosomal transport and fusion processes, e.g., as intracellular calcium sources. Currently, however, the exact physiological roles of TRPML channels and TPCs remain quite elusive, and whether TRPML channels are purely endolysosomal ion channels or whether they may also be functionally active at the plasma membrane in vivo remains to be determined.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.192880.

  • ABBREVIATIONS:

    LSD
    lysosomal storage disease
    CFTR
    cystic fibrosis transmembrane conductance regulator
    LRO
    lysosome-related organelle
    LTS
    lysosomal-targeting sequence
    ML
    mucolipidosis
    ML IV
    ML type IV
    MCOLN
    mucolipin
    NAADP
    nicotinic acid adenine dinucleotide phosphate
    PI(3,5)P2
    phosphatidylinositol 3,5-bisphosphate
    PRD
    proline-rich domain
    SNP
    single-nucleotide polymorphism
    TMD
    transmembrane domain
    TPC
    two-pore channel
    TRP
    transient receptor potential
    SF-21
    4-chloro-N-(2-morpholin-4-yl-cyclohexyl)benzenesulfonamide
    SF-41
    1-(2,4-dimethylphenyl)-4-piperidin-1-yl-sulfonyl piperazine
    SF-51
    2-[2-oxo-2-(2,2,4-trimethylquinolin-1-yl)ethyl]isoindole-1,3-dione
    SF-81
    4,6-di-methyl-3-(2-methylphenyl)sulfonyl-1-propan-2-yl-pyridin-2-one
    ML-SA1
    2-[2-oxo-2-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethyl]isoindole-1, 3-dione
    VX-770
    N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

  • Received March 14, 2012.
  • Accepted April 17, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticlePerspectives in Pharmacology

TRPML Channels and TPCs in Endolysosomal Cation Homeostasis

Christian Grimm, Sami Hassan, Christian Wahl-Schott and Martin Biel
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 236-244; DOI: https://doi.org/10.1124/jpet.112.192880

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Research ArticlePerspectives in Pharmacology

TRPML Channels and TPCs in Endolysosomal Cation Homeostasis

Christian Grimm, Sami Hassan, Christian Wahl-Schott and Martin Biel
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 236-244; DOI: https://doi.org/10.1124/jpet.112.192880
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  • Article
    • Abstract
    • Introduction
    • Lysosomal Storage Disorders
    • The Identification of Mutations in the Trpml1 Gene as Causative for ML IV
    • Structural and Functional Aspects of TRPML Channels
    • Toward a Physiological Role for TRPML Channels and TPCs
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