Nomenclature: TRPML1

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 1 580 19p13.3-p13.2 MCOLN1 mucolipin 1 1,23
Mouse 6 1 580 8 A1.1 Mcoln1 mucolipin 1 13
Rat 6 1 580 12p12 Mcoln1 mucolipin 1
Previous and Unofficial Names
MCOLN1
Mucolipin1
ML1
TRP-ML1
Mucolipin-1
Database Links
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPML2 8,31
TRPML3 8,31
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Hsc70; HSP40 24
ALG2, alpha-1,3/1,6-mannosyltransferase 26
TPCN2, two pore segment channel 2 (TPC2) 30
LAPTMs, lysosomal multispanning membrane proteins 27
Functional Characteristics
TRPML1Va: γ = 40 pS and 76-86 pS at very negative holding potentials with Fe2+ and monovalent cations as charge carriers, respectively; conducts Na+≅ K+>Cs+ and divalent cations (Ba2+>Mn2+>Fe2+>Ca2+> Mg2+> Ni2+>Co2+> Cd2+>Zn2+>>Cu2+) protons; monovalent cation flux suppressed by divalent cations (e.g. Ca2+, Fe2+); inwardly rectifying
Ion Selectivity and Conductance
Species:  Human
Rank order:  K+ [84.3 - 92.4 pS] > Na+ [80.8 - 82.6 pS] > Ba2+ [44.6 pS] > Sr2+ [37.2 pS] > Ca2+ [32.5 - 34.4 pS]
References:  16,18
Species:  Mouse
Rank order:  Ca2+ > K+ = Na+ > Cs+
References:  29,32
Ion Selectivity and Conductance Comments
The activating mutation (V432P) and surface-expressing mutation (L15L/AA-L577L/AA, abbreviated as TRPML1–4A) channels are unlikely to affect the pore properties and are currently accepted as representing the wild type TRPML1 permeation properties if such data are not available for wild type TRPML1.

Ion selectivity in mouse was measured using the activating mutation (V432P) of TRPML1. Ion conductance (pS) was recorded at between 11 (from -80 to 40 mV) and 76 (from -140 to -100 mV) in the modified (pH 4.6) “Tyrode” solution (extracellular/luminal) [28-29,32]. Human TRPML1 ion selectivity is Ba2+>Mn2+>Fe2+=Ca2+=Mg2+>Ni2+ =Co2+=Cd2+>Zn2+>>Cu2+ (at pH 4.6, with pS measured at 32-40 in the presence of 30-105mM Fe2+, measured using the activating mutation (V432P) of TRPML1) [9].
Voltage Dependence Comments
Activation is strong inwardly rectifying. Activation is instantaneous at negative voltages and there is no time-dependent inactivation at negative voltages [29].
Activators (Human)
TRPML1Va: Constitutively active, current potentiated by extracellular acidification (equivalent to intralysosomal acidification)
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
phosphatidyl (3,5) inositol biphosphate Hs Activation 7.32 pEC50 - - 10
pEC50 7.32 (EC50 4.8x10-8 M) Also activates other TRPMLs [10]
Activator Comments
ML-SA1 (ligand ID: 6386, 1-20µM), SF-22 (ligand ID: 6389, 100µM) and SF-51 (ligand ID: 6387, 100µM) all activate TRPML1 in various cells and heterologous expression systems [15,21]. Proton and sphingosine can up-regulate the channel activity in the presence of agonists.
Gating Inhibitor Comments
Sphingomyelins (20µM, [21]), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2, 0.2µM, [32]) and verapamil (ligand ID: 2406, 1µM, [29]) are reported to act as gating inhibitors of TRPML1. PI(4,5)P2 affects Popen of TRPML1 and verapamil affects the voltage-dependence of the TRPML1-V432P currents.
Channel Blocker Comments
The trivalent blocker, La3+ (100 µm), inhibits >80% of ITRPML1-C430P, ITRPML1-C431P, ITRPML1-V432P, and ITRPML1-R427P in a heterologous expression system [11].
Tissue Distribution
Brain, skeletal muscle, colon, thymus, liver, lung, leukocytes
Species:  Human
Technique:  Northern Blot
References:  1
Ubiquitously expressed in every tissue with the highest levels of expression located in the brain, kidney, spleen, liver, and heart. Subcellular cellular localization: late endosomes and lysosomes.
Species:  Mouse
Technique:  Northern blot and RT-PCR
References:  1,20
Functional Assays
Inside-out excised-patch recordings
Species:  Mouse
Tissue:  HEK293T cells expressing wild-type TRPML1 or TRPML1–4A channels
Response measured:  Single channel TRPML1 currents
References:  32
Whole-endolysosome patch-clamp (human or mouse). In the whole-endolysosome configuration, “inward” currents indicate the cations flowing out of the lumen to the cytoplasm.
Species:  Human
Tissue:  Human fibroblasts, mouse macrophages, or COS1 cells transfected with TRPML1
Response measured:  Endogenous and recombinant TRPML1 currents; activation by PI(3,5)P2or ML-SA1.
References:  10,21,28
GCaMP3-TRPML1 Ca2+ imaging
Species:  Mouse
Tissue:  CHO cells transfected with GCaMP3-TRPML1
Response measured:  Agonist-induced lysosomal Ca2+ release
References:  21
Fe2+ imaging
Species:  Mouse
Tissue:  HEK293 expressing several proline substitutions (activation mutations) of TRPML1 channels
Response measured:  Fe2+ influx
References:  9,11
Ca2+ imaging (human and mouse)
Species:  Human
Tissue:  HEK293T expressing several proline (activation substitutions) or surface-expressing (TRPML1-4A) mutant TRPML1 channels
Response measured:  Constitutive or agonist-induced Ca2+ influx
References:  11,14
Whole-cell recordings
Species:  Mouse
Tissue:  HEK293T cells expressing surface-expressing mutant TRPML1 (TRPML1-L15L/AA-L577L/AA, abbreviated as TRPML1–4A) channels
Response measured:  SF-51 and ML-SA1-activated whole cell currents
References:  21
Physiological Functions
Lysosomal exocytosis: an involvement in membrane sorting and/or the late steps of endocytosis is suggested by defects in transport along the lysosomal pathway in Mucolipidosis Type IV patients.
Species:  Human
Tissue:  Fibroblasts and HEK293T cells expressing activating mutations of TRPML1
References:  2,11,17
Membrane trafficking in the late endocytic pathways including lysosome-to-Golgi retrograde trafficking and lysosome biogenesis
Species:  Human
Tissue:  Fibroblasts
References:  4
Defective autophagy and mitochondrial fragmentation in fibroblasts and neurons lacking TRPML1 (human and mouse)
Species:  Human
Tissue:  Neurons and fibroblasts
References:  7,25
Lysosomal Ca2+ release (human and mouse)
Species:  Human
Tissue:  Fibroblasts, macrophages, or CHO cells transfected with TRPML1
References:  21
Lysosomal Fe2+ /Zn2+ homeostasis
Species:  Human
Tissue:  Transfected HEK293T cells and fibroblasts
References:  9,12
Gastric acid secretion
Species:  Mouse
Tissue:  Gastric mucosa
References:  3
Constitutive cathepsin B release in cells lacking TRPML1
Species:  Human
Tissue:  HEK293T cells
References:  6
Lysosomal H+ homeostasis
Species:  Human
Tissue:  Fibroblasts
References:  5,19
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001406 abnormal gait PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0005209 abnormal gastric mucosa morphology PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0003632 abnormal nervous system morphology PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001330 abnormal optic nerve morphology PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0003731 abnormal retinal outer nuclear layer morphology PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0008843 absent subcutaneous adipose tissue PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001262 decreased body weight PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0000774 decreased brain size PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0004819 decreased skeletal muscle mass PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0002795 dilated cardiomyopathy PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001270 distended abdomen PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0000539 distended urinary bladder PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0000755 hindlimb paralysis PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001505 hunched posture PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0004731 increased circulating gastrin level PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0005202 lethargy PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001513 limb grasping PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0002083 premature death PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001326 retinal degeneration PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0001407 short stride length PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0008511 thin retinal inner nuclear layer PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0008513 thin retinal inner plexiform layer PMID: 17924347 
Mcoln1tm1Sasl Mcoln1tm1Sasl/Mcoln1tm1Sasl
involves: 129S6/SvEvTac * C57BL/6
MGI:1890498  MP:0000746 weakness PMID: 17924347 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Mucolipidosis IV
OMIM:  252650
Orphanet:  578
Role: 
References:  1,23
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human A5534G (genomic seq.) 22
Missense Human 454-469del 22
Missense Human R322L 22
Missense Human R172X 22
Missense Human R102X 22
Missense Human T232P Impaired TRPML1 channel function 9,22
Missense Human V446L Impaired TRPML1 channel function 9,22
Missense None D362Y Impaired TRPML1 channel function 9,22
Missense Human F465L Impaired TRPML1 channel function 9,22
Missense Human F408del Impaired TRPML1 channel function 9,22
Truncation Human del 511-6499 (genomic seq) 22
Truncation Human 1569insGCCCTGCTGCG (mRNA) 22
Truncation Human 1334-1335insT (mRNA) 22
Truncation Human 598-599delCC (mRNA) 22
Disease:  Niemann-Pick diseases
Role: 
References:  21
Mutations not determined
Clinically-Relevant Mutations and Pathophysiology Comments
Mucolipidosis IV is associated with mutations in TRPML1. For detailed molecular genetics involving Mucolipidosis IV, see the link to OMIM ID 252650 above.

REFERENCES

1. 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 (1): 118-23. [PMID:10973263]

2. Bargal R, Bach G. (1997) Mucolipidosis type IV: abnormal transport of lipids to lysosomes. J. Inherit. Metab. Dis.20 (5): 625-32. [PMID:9323557]

3. Chandra M, Zhou H, Li Q, Muallem S, Hofmann SL, Soyombo AA. (2011) A role for the Ca2+ channel TRPML1 in gastric acid secretion, based on analysis of knockout mice. Gastroenterology140 (3): 857-67. [PMID:21111738]

4. Chen CS, Bach G, Pagano RE. (1998) Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc. Natl. Acad. Sci. U.S.A.95 (11): 6373-8. [PMID:9600972]

5. Cheng X, Shen D, Samie M, Xu H. (2010) Mucolipins: Intracellular TRPML1-3 channels. FEBS Lett.584 (10): 2013-21. [PMID:20074572]

6. Colletti GA, Miedel MT, Quinn J, Andharia N, Weisz OA, Kiselyov K. (2012) Loss of lysosomal ion channel transient receptor potential channel mucolipin-1 (TRPML1) leads to cathepsin B-dependent apoptosis. J. Biol. Chem.287 (11): 8082-91. [PMID:22262857]

7. 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 (2): 370-7. [PMID:20600908]

8. 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]

9. 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]

10. 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]

11. 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 (46): 32040-52. [PMID:19638346]

12. 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 (45): 34304-8. [PMID:20864526]

13. Falardeau JL, Kennedy JC, Acierno JS, 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 Genomics3 (1): 3. [PMID:11897010]

14. 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]

15. 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]

16. 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 (1-2): 183-7. [PMID:12459486]

17. 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 (4): 339-48. [PMID:16914343]

18. LaPlante JM, Ye CP, Quinn SJ, Goldin E, Brown EM, Slaugenhaupt SA, Vassilev PM. (2004) Functional links between mucolipin-1 and Ca2+-dependent membrane trafficking in mucolipidosis IV. Biochem. Biophys. Res. Commun.322 (4): 1384-91. [PMID:15336987]

19. Puertollano R, Kiselyov K. (2009) TRPMLs: in sickness and in health. Am. J. Physiol. Renal Physiol.296 (6): F1245-54. [PMID:19158345]

20. 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]

21. 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]

22. Slaugenhaupt SA. (2002) The molecular basis of mucolipidosis type IV. Curr. Mol. Med.2 (5): 445-50. [PMID:12125810]

23. Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno JS, Bove C, Kaneski CR, Nagle J, Bromley MC, Colman M, Schiffmann R, Slaugenhaupt SA. (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum. Mol. Genet.9 (17): 2471-8. [PMID:11030752]

24. 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]

25. Vergarajauregui S, Connelly PS, Daniels MP, Puertollano R. (2008) Autophagic dysfunction in mucolipidosis type IV patients. Hum. Mol. Genet.17 (17): 2723-37. [PMID:18550655]

26. 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 (52): 36357-66. [PMID:19864416]

27. 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 (Pt 3): 459-68. [PMID:21224396]

28. 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. Cell151 (2): 372-83. [PMID:23063126]

29. 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. U.S.A.104 (46): 18321-6. [PMID:17989217]

30. 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 (26): 22934-42. [PMID:21540176]

31. 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]

32. Zhang X, Li X, Xu H. (2012) Phosphoinositide isoforms determine compartment-specific ion channel activity. Proc. Natl. Acad. Sci. U.S.A.109 (28): 11384-9. [PMID:22733759]

To cite this database page, please use the following:

Haoxing Xu, David E. Clapham.
Transient Receptor Potential channels: TRPML1. Last modified on 07/02/2014. Accessed on 31/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=501.

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