A Novel Mode of TRPML3 Regulation by Extracytosolic PH Absent in the Varitint-waddler Phenotype

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2008 Mar 29

PMID 18369318

Citations 55

Authors

Hyun Jin Kim

Qin Li

Sandra Tjon-Kon-Sang

Insuk So

Kirill Kiselyov

Abigail A Soyombo

Shmuel Muallem

Affiliations

Soon will be listed here.

Abstract

TRPML3 belongs to the TRPML subfamily of the transient receptor potential (TRP) channels. The A419P mutation in TRPML3 causes the varitint-waddler phenotype as a result of gain-of-function mutation (GOF). Regulation of the channels and the mechanism by which the A419P mutation leads to GOF are not known. We report here that TRPML3 is a Ca(2+)-permeable channel with a unique form of regulation by extracytosolic (luminal) H(+) (H(+)(e-cyto)). Regulation by H(+)(e-cyto) is mediated by a string of three histidines (H252, H273, H283) in the large extracytosolic loop between transmembrane domains (TMD) 1 and 2. Each of the histidines has a unique role, whereby H252 and H273 retard access of H(+)(e-cyto) to the inhibitory H283. Notably, the H283A mutation has the same phenotype as A419P and locks the channel in an open state, whereas the H283R mutation inactivates the channel. Accordingly, A419P eliminates regulation of TRPML3 by H(+)(e-cyto), and confers full activation to TRPML3(H283R). Activation of TRPML3 and regulation by H(+)(e-cyto) are altered by both the alpha-helix-destabilizing A419G and the alpha-helix-favouring A419M and A419K. These findings suggest that regulation of TRPML3 by H(+)(e-cyto) is due to an effect of the large extracytosolic loop on the orientation of fifth TMD and thus pore opening and show that the GOF of TRPML3(A419P) is due to disruption of this communication.

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References

Fares H, GREENWALD I . Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet. 2001; 28(1):64-8. DOI: 10.1038/ng0501-64. View

Sun-Wada G, Wada Y, Futai M . Diverse and essential roles of mammalian vacuolar-type proton pump ATPase: toward the physiological understanding of inside acidic compartments. Biochim Biophys Acta. 2004; 1658(1-2):106-14. DOI: 10.1016/j.bbabio.2004.04.013. View

Owsianik G, Talavera K, Voets T, Nilius B . Permeation and selectivity of TRP channels. Annu Rev Physiol. 2006; 68:685-717. DOI: 10.1146/annurev.physiol.68.040204.101406. View

Cable J, Steel K . Combined cochleo-saccular and neuroepithelial abnormalities in the Varitint-waddler-J (VaJ) mouse. Hear Res. 1998; 123(1-2):125-36. DOI: 10.1016/s0378-5955(98)00107-5. View

Grimm C, Cuajungco M, van Aken A, Schnee M, Jors S, Kros C . A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proc Natl Acad Sci U S A. 2007; 104(49):19583-8. PMC: 2148332. DOI: 10.1073/pnas.0709846104. View

Di Palma F, Belyantseva I, Kim H, Vogt T, Kachar B, Noben-Trauth K . Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice. Proc Natl Acad Sci U S A. 2002; 99(23):14994-9. PMC: 137533. DOI: 10.1073/pnas.222425399. View

Bargal R, Avidan N, Ben-Asher E, Olender Z, Zeigler M, Frumkin A . Identification of the gene causing mucolipidosis type IV. Nat Genet. 2000; 26(1):118-23. DOI: 10.1038/79095. View

Manzoni M, Monti E, Bresciani R, Bozzato A, Barlati S, Bassi M . Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization. FEBS Lett. 2004; 567(2-3):219-24. DOI: 10.1016/j.febslet.2004.04.080. View

den Dekker E, Hoenderop J, Nilius B, Bindels R . The epithelial calcium channels, TRPV5 & TRPV6: from identification towards regulation. Cell Calcium. 2003; 33(5-6):497-507. DOI: 10.1016/s0143-4160(03)00065-4. View

10.

Nilius B, Owsianik G, Voets T, Peters J . Transient receptor potential cation channels in disease. Physiol Rev. 2007; 87(1):165-217. DOI: 10.1152/physrev.00021.2006. View

11.

Nagata K, Zheng L, Madathany T, Castiglioni A, Bartles J, Garcia-Anoveros J . The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration. Proc Natl Acad Sci U S A. 2007; 105(1):353-8. PMC: 2224216. DOI: 10.1073/pnas.0707963105. View

12.

Venkatachalam K, Hofmann T, Montell C . Lysosomal localization of TRPML3 depends on TRPML2 and the mucolipidosis-associated protein TRPML1. J Biol Chem. 2006; 281(25):17517-17527. PMC: 4196876. DOI: 10.1074/jbc.M600807200. View

13.

Kiselyov K, Soyombo A, Muallem S . TRPpathies. J Physiol. 2006; 578(Pt 3):641-53. PMC: 2151344. DOI: 10.1113/jphysiol.2006.119024. View

14.

Kim H, Li Q, Tjon-Kon-Sang S, So I, Kiselyov K, Muallem S . Gain-of-function mutation in TRPML3 causes the mouse Varitint-Waddler phenotype. J Biol Chem. 2007; 282(50):36138-42. DOI: 10.1074/jbc.C700190200. View

15.

Song Y, Dayalu R, Matthews S, Scharenberg A . TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes. Eur J Cell Biol. 2006; 85(12):1253-64. DOI: 10.1016/j.ejcb.2006.08.004. View

16.

Hersh B, Hartwieg E, Horvitz H . The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types. Proc Natl Acad Sci U S A. 2002; 99(7):4355-60. PMC: 123652. DOI: 10.1073/pnas.062065399. View

17.

Xu H, Delling M, Li L, Dong X, Clapham D . Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice. Proc Natl Acad Sci U S A. 2007; 104(46):18321-6. PMC: 2084341. DOI: 10.1073/pnas.0709096104. View

18.

Paroutis P, Touret N, Grinstein S . The pH of the secretory pathway: measurement, determinants, and regulation. Physiology (Bethesda). 2004; 19:207-15. DOI: 10.1152/physiol.00005.2004. View

19.

Pedersen S, Owsianik G, Nilius B . TRP channels: an overview. Cell Calcium. 2005; 38(3-4):233-52. DOI: 10.1016/j.ceca.2005.06.028. View