Trpml1

Abstract

TRPML1 (or mucolipin 1) is the first member of the TRP family of ion channels that was found to function in the lower portions of the endocytic pathway. Mutations in the gene coding for TRPML1 (MCOLN1) cause the lysosomal storage disease mucolipidosis type IV (MLIV). TRPML1 localization in the lysosomes and the similarity of mucolipidosis type IV phenotype to lysosomal storage diseases whose origin has been directly linked to lysosomal dysfunction, suggest that TRPML1 activity drives some vitally important processes within the endocytic machinery. The specific aspect(s) of TRPML1 activity that make it indispensable for the proper function of the endocytic pathway as well as the specific aspect(s) of the endocytic activity that depend on TRPML1 are currently being discussed. Among the candidates are: membrane fusion within the lower portion of the endocytic pathway possibly mediated by Ca(2+) release through TRPML1, or regulation of lysosomal ion homeostasis (pH or Fe content) by TRPML1. In addition to delineating the mechanisms of MLIV pathogenesis, identifying the role of TRPML1 in the endocytic pathway will lead to important developments in our understanding of the endocytic pathway and, due to the neurodegenerative nature of MLIV, of the integrative function of the cell. Moreover, molecular modulators of TRPML1 function may lead to novel approaches to modulating biological processes that depend on the endocytic pathway such as growth factor signaling. The present review will focus on the recent developments in identifying the TRPML1 function.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…-permeable nonselective cation channel that is impermeable for protons and shows a strong, inwardly rectifying IV curve (see Colletti and Kiselyov, 2011). TRPML1 homomultimerizes as well as heteromultimerizes with TRPML2 and TRPML3 .…”

The intracellular Ca2+channels of membrane traffic

“…The TRPML family was established with the identification of TRPML1. 47,48 TRPML1, the first member of the mucolipins, was cloned in 1999, as a result of genetic analyses of patient tissues with a genetic disease called Mucolipidosis type IV (MLIV). 49,50 MLIV is a lysosomal storage disease linked to buildup of poorly characterized material throughout the patient's tissue in the form of storage bodies.…”

“…A number of excellent review articles on TRPML channels published recently provide comprehensive analysis of TRPML localization, traffic and possible function. 47,48,[53][54][55] In the present review, we will focus on their Ca 2+ transport function and the evidence for its role in membrane fusion.…”

“…Models of the functional consequences of its effect on TRPML1 and membrane traffic have been discussed before. 47 In brief, the PI(3,5)P2-TRPML1 interaction may be a priming mechanism for newly delivered TRPML1 into lysosomes, or it may serve as a proximity sensor for organelles in the endocytic pathway. According to this model, the interacting membranes are matched by Rab and SNARE proteins, followed by PI(3,5)P2 binding to the C-termini of TRPML1, Ca 2+ release and conformational changes in SNARE proteins which drive membrane fusion.…”

Evolutionary dynamics of metazoan TRP channels

“…Mucolipidosis type IV disease, an autosomal-recessive neurodegenerative lysosomal storage disorder, is caused by mutations in TRPML1. TRPML1 is a calcium and iron permeable intracellular channel in lysosomes, and thus, loss-of-function impairs endosomal/lysosomal function and autophagy [10]. Polycystic kidney disease (PKD), the most common inherited kidney disease, is associated with a mutation in TRPP2.…”