TABLE 1

Summary of TPC and TRPML channel characteristics

Family Name	TRP			TPC
Family Name	TRPML1	TRPML2	TRPML3	TPC1	TPC2
Synonyms	MCOLN1	MCOLN2	MCOLN3	TPCN1	TPCN2
Length (aa) Hs	580	566	553	888 (816)	752
Length (aa) Mm	580	566 (538)	553	817	731
Seq motifs	Serine-lipase; lysosomal targeting sequence (N and C terminal); PRD	Lysosomal targeting sequence (N terminal in Mm)	N.D.	Legume lectins β-chain signature; lysosomal targeting sequence (N and C terminal)	Lysosomal targeting sequence (N terminal)
Localization	Lysosomes; LRO?	PM (in vitro); lysosomes?; LRO?; endosomes	PM (in vitro); (early/late) endosomes; melanosomes?	Endosomes	Lysosomes; LRO? melanosomes?
Tissue distribution	Ubiquitous	Thymus, spleen, kidney, trachea, liver, lung, colon, testis, thyroid, inner ear?, lymphocyte B cells	Hair cells of the inner ear, organ of corti, utricle, stria vascularis, (skin) melanocytes, kidney, lung, liver, olfactory bulb, nasal cavity, thymus, colon, trachea, brain?	Ubiquitous	Ubiquitous
Activators	NAADP?; PI(3,5)P₂; ML-SA1; SF-22; SF-51 (30 μM)	PI(3,5)P₂; ML-SA1; SF-21; SF-41; SF-81	PI(3,5)P₂; ML-SA1; SN-1; SN-2; SF-11; SF-21; SF-22; SF-23; SF-24; SF-31; SF-32; SF-33; SF-41; SF-51; SF-61; SF-71; SF-81	NAADP	NAADP
Inhibitors	Sphingomyelins	N.D.	Low pH and high extracellular Na⁺	Ned-19	Ned-19
Regulators	Low pH, Smases and sphingosine potentiate	Low pH potentiates	Low extracellular Na⁺ potentiates activation by chemical compounds	N.D.	Low pH and Ca²⁺ potentiate?
Disease mutations or polymorphisms associated with a phenotype	ML IV is associated with mutations in HsTRPML1; symptoms include severe psychomotor retardation and retinal degeneration	N.D.	Deafness, circling behavior, head bobbing, and coat color dilution is associated with mutations in MmTRPML3 (Varitint-waddler mutations Va and Va^J)	N.D.	Polymorphisms in HsTPC2 are associated with blond versus brown hair
Gain-of-function mutants	V432P	A396P (Mm)	Va (A419P) and Va^J (A419P + I362T)	N.D.	N.D.
Disease-associated loss-of-function mutants	T232P, D362Y, F465L, R403C, F408Δ	N.D.	N.D.	N.D.	N.D.
Knockout mouse models	Knockout mice display enlarged vacuoles, psychomotor defects, and retinal degeneration	N.D.	Knockout mice display no auditory or vestibular phenotype and no coat color dilution	N.D.	Pancreatic β-cells from TPC2 knockout mice are NAADP insensitive
Functions	Role in sorting/transport in late endocytic pathway; regulates lysosomal lipid and cholesterol trafficking; endolysosomal pH regulation and cation/heavy metal (iron) homeostasis?; NAADP receptor?	Endolysosomal pH regulation and cation homeostasis?; vesicle fusion and transport?	Overexpression increases endosomal pH; endosomal pH regulation and cation homeostasis?; vesicle fusion and transport?	NAADP receptor complex?; vesicle fusion and transport?; endolysosomal pH and Ca²⁺ regulation?	NAADP receptor complex?; vesicle fusion and transport?; endolysosomal pH and Ca²⁺ regulation?
Interacting proteins	TRPML2, TRPML3, TPC1?, TPC2; LAPTMs; Hsp40; Hsc70	TRPML1, TRPML3, Hsc70?	TRPML1, TRPML2, TPC1?, TPC2, Hsc70?	TRPML1, TRPML3	TRPML1, TRPML3

N.D., not determined; PM, plasma membrane; SF-11, (3-(4-chlorophenyl)-5-methyl-4-[2-(4-methylphenyl)sulfonylpyrazol-3-yl]-1,2-oxazole); SN-1, (N-tert-butyl-3-(3-tert-butyl-1-methyl-7-oxo-4H-pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxybenzenesulfonamide); SF-22, (5-chloro-N-(2-piperidin-1-ylphenyl)thiophene-2-sulfonamide); SF-31, (1-(4-ethoxynaphthalen-1-yl)sulfonylazepane); SF-23, (5-chloro-N-(2-morpholin-4-ylphenyl)thiophene-2-sulfonamide); SF-32, (1-(4-ethoxy-2,3-dimethylphenyl)sulfonylpiperidine); SF-24, (4-methyl-N-(2-phenylphenyl)benzenesulfonamide); SF-33, (5-chloro-N,N-diethyl-4-methyl-2-propoxybenzenesulfonamide); SF-61, (4-(2-methoxyphenyl)spiro[3,4-dihydropyrazole-5,8′-6,7-dihydro-5H-benzo[7]annulene]-9′-one); SF-71, ([2-tert-butyl-5-methyl-4-(4-methylphenyl)sulfonylpyrazol-3-yl]butanoate); SN-2, (5-mesityl-3-oxa-4-azatricyclo[5.2.1.0∼2,6∼]dec-4-ene).