Nomenclature: TRPML2

Family: Transient Receptor Potential channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 566 1p22.3 MCOLN2 mucolipin 2 2
Mouse 6 1 566 3 H2 Mcoln2 mucolipin 2 2
Rat 6 1 566 2q44 Mcoln2 mucolipin 2
Previous and Unofficial Names
MCOLN2
Mucolipin2
FLJ36691
TRP-ML2
LOC292168
MGC124828
Mcoln2_predicted
mucolipin 2
mucolipin 2 (predicted)
mucolipin-2
mucolipidin 2
3300002C04Rik
AI549968
C86638
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPML1 1,15
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
TRPML3 1,15
Hsc70 (potentially) 14
Functional Characteristics
TRPML1Va: Conducts Na+; monovalent cation flux suppressed by divalent cations; inwardly rectifying
Ion Selectivity and Conductance Comments
Selectivity rank order: Na+ ~ K+ ~ Cs+ [3-4,6], Ca2+ ~Fe2+ [3] (measured using the activating mutation, A369P, of TRPML2).

The plasma membrane-localised and consitutively active TRPML2 mutant (A396P), corresponding to the Va mutation in TRPML3, is a cation nonselective, ion channel [5]. This mutation is unlikely to affect the pore properties and is currently accepted as representing the wild type TRPML2 permeation properties if such data are not available for wild-type TRPML2 channels.

Wild type TRPML2 appears to primarily span membranes of intracellular lysosomes and endosomes.
Voltage Dependence Comments
Strong inwardly rectifying; activation only at negative voltages.
Activators (Human)
TRPML2Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)
Activator Comments
Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) [4], SF-21, SF-41, SF-81 [6] and ML-SA1 [12] are all reported to be activators of TRPML2.

In a heterologous overexpression system, TRPML2 can be weakly activated by Na+ removal followed by re-addition [6].
Tissue Distribution
B cells, T cells, primary splenocytes, mastocytoma, and myeloma cell lines.
Species:  Mouse
Technique:  RT-PCR
References:  10
Thymus, liver, kidney, heart, spleen. Subcellular cellular localization: recycling endosomes, late endosomes and lysosomes.
Species:  Mouse
Technique:  RT-PCR
References:  11
Functional Assays
Whole-cell patch clamp recordings (human and mouse)
Species:  Human
Tissue:  HEK293 cells
Response measured:  Whole-cell currents from cells expressing TRPML2 or TRPML2Va (A369P) channels
References:  3
Whole-cell patch clamp recordings
Species:  Mouse
Tissue:  HEK293 cells expressing TRPML2 channels
Response measured:  currents activated by Na+ removal followed by re-addition, or SF-41
References:  6
Ca2+ imaging (human and mouse)
Species:  Human
Tissue:  HEK293 cells expressing TRPML2 or TRPML2Va (A369P) channels
Response measured:  Ca2+ influx
References:  5-7
Whole-endolysosome patch-clamp. In the whole-endolysosome configuration, “inward” currents indicate the cations flowing out of the lumen to the cytoplasm.
Species:  Mouse
Tissue:  COS1 cells transfected with TRPML2
Response measured:  TRPML2 currents; activation by PI(3,5)P2 or ML-SA1
References:  4,12
Physiological Functions
Putative role in TRPML3 localisation to lysosomes through heteromerisation.
Species:  Human
Tissue:  HEK cells.
References:  13
Membrane trafficking in late endocytic pathways and Arf6-regulated recycling pathways.
Species:  Human
Tissue:  HeLa cells
References:  8
Constitutively active TRPML2 induces cell death.
Species:  Human
Tissue:  Drosophila S2 cells expressing human TRPML2
References:  9
Biologically Significant Variants
Type:  Splice variant
Species:  Mouse
Description:  Isoform 1
Amino acids:  566
Nucleotide accession: 
Protein accession: 
References:  5
Type:  Splice variant
Species:  Mouse
Description:  Isoform 2
Amino acids:  538
Nucleotide accession: 
Protein accession: 
References:  11
Biologically Significant Variant Comments
Currents have only been reported from the long splice variant (NP_080932, [5]).

REFERENCES

1. Curcio-Morelli C, Zhang P, Venugopal B, Charles FA, Browning MF, Cantiello HF, Slaugenhaupt SA. (2010) Functional multimerization of mucolipin channel proteins. J. Cell. Physiol.222 (2): 328-35. [PMID:19885840]

2. 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. U.S.A.99 (23): 14994-9. [PMID:12403827]

3. 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. Nature455 (7215): 992-6. [PMID:18794901]

4. Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M et al.. (2010) PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome. Nat Commun1: 38. [PMID:20802798]

5. Grimm C, Cuajungco MP, van Aken AF, Schnee M, Jörs S, Kros CJ, Ricci AJ, Heller S. (2007) A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proc. Natl. Acad. Sci. U.S.A.104 (49): 19583-8. [PMID:18048323]

6. Grimm C, Jörs S, Guo Z, Obukhov AG, Heller S. (2012) Constitutive activity of TRPML2 and TRPML3 channels versus activation by low extracellular sodium and small molecules. J. Biol. Chem.287 (27): 22701-8. [PMID:22753890]

7. Grimm C, Jörs 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 (2): 135-48. [PMID:20189104]

8. Karacsonyi C, Miguel AS, Puertollano R. (2007) Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs. Traffic8 (10): 1404-14. [PMID:17662026]

9. Lev S, Zeevi DA, Frumkin A, Offen-Glasner V, Bach G, Minke B. (2010) Constitutive activity of the human TRPML2 channel induces cell degeneration. J. Biol. Chem.285 (4): 2771-82. [PMID:19940139]

10. Lindvall JM, Blomberg KE, Wennborg A, Smith CI. (2005) Differential expression and molecular characterisation of Lmo7, Myo1e, Sash1, and Mcoln2 genes in Btk-defective B-cells. Cell. Immunol.235 (1): 46-55. [PMID:16137664]

11. 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. [PMID:19763610]

12. 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 Commun3: 731. [PMID:22415822]

13. Venkatachalam K, Hofmann T, Montell C. (2006) Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. J. Biol. Chem.281 (25): 17517-27. [PMID:16606612]

14. 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 (2): 344-53. [PMID:19117012]

15. Zeevi DA, Lev S, Frumkin A, Minke B, Bach G. (2010) Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy. J. Cell. Sci.123 (Pt 18): 3112-24. [PMID:20736310]

To cite this database page, please use the following:

Haoxing Xu, David E. Clapham.
Transient Receptor Potential channels: TRPML2. Last modified on 13/08/2013. Accessed on 01/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=502.

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