TRPML1 | Transient Receptor Potential Cation Channel Subfamily ML Member 1

Mucolipin-1, also called TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1) is a lysosomal cation/Ca²⁺ channel: It is proposed to play a major role in Ca²⁺ release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy. The channel is constitutively active and the current potentiated by extracellular acidification (equivalent to intralysosomal acidification).

Gene:
MCOLN1

Human Protein:
UniProt Q8IZK6

Tissue:
The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, it is widely expressed in adult and fetal tissues, highest expression level in adrenal gland

Function/ Application:
TRPML1 functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca²⁺, Na⁺, K⁺, and H⁺, as well as diverse metal ions as Fe²⁺, Zn²⁺, Ni²⁺, and is modulated by changes in Ca²⁺ concentration. TRPML1 is believed to channel iron ions across the endosome/lysosome membrane into the cell and so its malfunction causes cellular iron deficiency. TRPML1 is probably involved in Zn²⁺ uptake into lysosomes and required for efficient uptake of large particles in macrophages in which Ca²⁺ release from the lysosomes triggers lysosomal exocytosis. The channel seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy

Pathology:
Mucolipidosis type IV, Niemann-Pick disease , leukomalacia, yunis-varon syndrome, cerebral palsy, ataxic, autosomal recessive

Accessory subunits:
Can heterooligomerize with MCOLN2 (TRPML2) or MCOLN3 (TRPML3)

Interaction:
PDCD6, TMEM163, LAPTM4B, TPC1, TPC2

Modulator:
In lysosomes activated by PtdIns(3,5)P2 (Phosphatidylinositol 3,5-bisphosphate) and at the plasma membrane inhibited by PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate). activators: ML SA1, MK6-83, SF-22, SF-51, blocker: La^3+,

Assays:
Patch Clamp: whole lysosome recording

Recommended Reviews:
International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels., Pharmacol Rev 55(4):591-6 Clapham, et al. 2003