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TRPML2

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Target id: 502

Nomenclature: TRPML2

Family: Transient Receptor Potential channels (TRP)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 566 1p22.3 MCOLN2 mucolipin TRP cation channel 2 2
Mouse 6 1 566 3 H2 Mcoln2 mucolipin 2 2
Rat 6 1 566 2q44 Mcoln2 mucolipin TRP cation channel 2
Previous and Unofficial Names Click here for help
MCOLN2 | mucolipin 2 | mucolipidin 2
Database Links Click here for help
Alphafold Q8IZK6 (Hs), Q8K595 (Mm)
ChEMBL Target CHEMBL4879493 (Hs)
Ensembl Gene ENSG00000153898 (Hs), ENSMUSG00000011008 (Mm), ENSRNOG00000015089 (Rn)
Entrez Gene 255231 (Hs), 68279 (Mm), 292168 (Rn)
Human Protein Atlas ENSG00000153898 (Hs)
KEGG Gene hsa:255231 (Hs), mmu:68279 (Mm), rno:292168 (Rn)
OMIM 607399 (Hs)
Pharos Q8IZK6 (Hs)
RefSeq Nucleotide NM_153259 (Hs), NM_026656 (Mm), NM_001005846 (Mm), NM_001039005 (Rn)
RefSeq Protein NP_694991 (Hs), NP_080932 (Mm), NP_001005846 (Mm), NP_001034094 (Rn)
UniProtKB Q8IZK6 (Hs), Q8K595 (Mm)
Wikipedia MCOLN2 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
TRPML1 1,17
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
TRPML3 1,17
Hsc70 (potentially) 16
Functional Characteristics Click here for help
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)

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
ML SA1 Small molecule or natural product Click here for species-specific activity table Hs Activation - - 1x10-5 -140.0 14
⤷ Conc range: 1x10-5 M [14]
Holding voltage: -140.0 mV
phosphatidyl (3,5) inositol bisphosphate Small molecule or natural product Click here for species-specific activity table Hs Activation - - 1x10-6 -140.0 4
⤷ Conc range: 1x10-6 M [4]
Holding voltage: -140.0 mV
ML2-SA1 Small molecule or natural product Immunopharmacology Ligand Hs Agonist 1.2 pEC50 - - 11
⤷ pEC50 1.2 [11]
Description: Determined by calcium imaging
Activator Comments
Phosphatidyl (3,5) inositol bisphosphate [4], SF-21, SF-41, SF-81 [6] and ML SA1 [14] 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].
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
PRU-12 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 pIC50 - - 12
⤷ pIC50 5.3 (IC50 5.28x10-6 M) [12]
PRU-10 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 pIC50 - - 12
⤷ pIC50 5.3 (IC50 5.4x10-6 M) [12]
estradiol 3-methyl ether Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.2 pIC50 - - 12
⤷ pIC50 5.2 (IC50 5.85x10-6 M) [12]
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Tissue Distribution Click here for help
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:  13
Functional Assays Click here for help
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:  4,14
Physiological Functions Click here for help
Putative role in TRPML3 localisation to lysosomes through heteromerisation.
Species:  Human
Tissue:  HEK cells.
References:  15
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 Click here for help
Type:  Splice variant
Species:  Mouse
Description:  Isoform 2
Amino acids:  538
Nucleotide accession:  NM_001005846
Protein accession:  NP_001005846
References:  13
Type:  Splice variant
Species:  Mouse
Description:  Isoform 1
Amino acids:  566
Nucleotide accession:  NM_026656
Protein accession:  NP_080932
References:  5
Biologically Significant Variant Comments
Currents have only been reported from the long splice variant (NP_080932, [5]).

References

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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 USA, 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. Nature, 455 (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 Commun, 1: 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 USA, 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. Traffic, 8 (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. Plesch E, Chen CC, Butz E, Scotto Rosato A, Krogsaeter EK, Yinan H, Bartel K, Keller M, Robaa D, Teupser D et al.. (2018) Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells. Elife, 7. [PMID:30479274]

12. Rühl P, Rosato AS, Urban N, Gerndt S, Tang R, Abrahamian C, Leser C, Sheng J, Jha A, Vollmer G et al.. (2021) Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors. Sci Rep, 11 (1): 8313. [PMID:33859333]

13. 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]

14. 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. [PMID:22415822]

15. 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]

16. 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]

17. 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]

Contributors

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