title: Role of TRPML and two-pore channels in endolysosomal cation homeostasis.
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.
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, 81377 Germany. chgrph@cup.uni-muenchen.de
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Sami
authors.initials: S
authors.lastname: Hassan
authors.forename: Christian
authors.initials: C
authors.lastname: Wahl-Schott
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002412:Cations / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009154:Mutation / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002412:Cations; D018129:Phosphatidylinositol Phosphates; D050051:Transient Receptor Potential Channels; C106336:phosphatidylinositol 3,5-diphosphate; D002118:Calcium