Traffic. 2009 Aug;10(8):1157-67. doi: 10.1111/j.1600-0854.2009.00924.x. Epub 2009 May 11.

The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Kim, H. J., Soyombo, A. A., Tjon-Kon-Sang, S., So, I., Muallem, S.,
["Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."]
TRPML3 is an inward rectifying Ca(2+) channel that is regulated by extracytosolic H(+). Although gain-of-function mutation in TRPML3 causes the varitint-waddler phenotype, the role of TRPML3 in cellular physiology is not known. In this study, we report that TRPML3 is a prominent regulator of endocytosis, membrane trafficking and autophagy. Gradient fractionation and confocal localization reveal that TRPML3 is expressed in the plasma membrane and multiple intracellular compartments. However, expression of TRPML3 is dynamic, with accumulation of TRPML3 in the plasma membrane upon inhibition of endocytosis, and recruitment of TRPML3 to autophagosomes upon induction of autophagy. Accordingly, overexpression of TRPML3 leads to reduced constitutive and regulated endocytosis, increased autophagy and marked exacerbation of autophagy evoked by various cell stressors with nearly complete recruitment of TRPML3 into the autophagosomes. Importantly, both knockdown of TRPML3 by siRNA and expression of the channel-dead dominant negative TRPML3(D458K) have a reciprocal effect, reducing endocytosis and autophagy. These findings reveal a prominent role for TRPML3 in regulating endocytosis, membrane trafficking and autophagy, perhaps by controlling the Ca(2+) in the vicinity of cellular organelles that is necessary to regulate these cellular events.
PMID: 19522758External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Validation: In vivo validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with endogenous proteins Assay with overexpressed proteins Reference
Cell or tissue Cell or tissue TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Species Region
TRPML1 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML3 Co-immunoprecipitation HEK293 Not specified Full-length Human Full-length 19522758
TRPML3 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 TRPML1 Co-immunoprecipitation HEK293 Human Full-length Not specified Full-length 19522758
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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