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The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

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Abstract

The discovery of the TRPML subfamily of ion channels has created an exciting niche in the fields of membrane trafficking, signal transduction, autophagy, and metal homeostasis. The TRPML protein subfamily consists of three members, TRPML1, TRPML2, and TRPML3, which are encoded by MCOLN1, MCOLN2, and MCOLN3 genes, respectively. They are non-selective cation channels with six predicted transmembrane domains and intracellular amino- and carboxyl-terminus regions. They localize to the plasma membrane, endosomes, and lysosomes of cells. TRPML1 is associated with the human lysosomal storage disease known as mucolipidosis type IV (MLIV), but TRPML2 and TRPML3 have not been linked with a human disease. Although TRPML1 is expressed in many tissues, TRPML3 is expressed in a varied but limited set of tissues, while TRPML2 has a more limited expression pattern where it is mostly detected in lymphoid and myeloid tissues. This review focuses on TRPML2 because it appears to play an important, yet unrecognized role in the immune system. While the evidence has been mostly indirect, we present and discuss relevant data that strengthen the connection of TRPML2 with cellular immunity. We also discuss the functional redundancy between the TRPML proteins, and how such features could be exploited as a potential therapeutic strategy for MLIV disease. We present evidence that TRPML2 expression may complement certain phenotypic alterations in MLIV cells and briefly examine the challenges of functional complementation. In conclusion, the function of TRPML2 still remains obscure, but emerging data show that it may serve a critical role in immune cell development and inflammatory responses.

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Acknowledgments

We are very grateful to Dr. Sean Murray (CSU Northridge) for reading and critiquing this manuscript. We thank Dr. Ehud Goldin (NIH/NHGRI) for providing WT and TRPML1-KD HGT-1 gastric adenocarcinoma cells. JV acknowledges research awards from CSUF EPOCHS Program, CSUF’s RCATT Office, and the CSU Statewide Student Research Competition. MPC and JS acknowledge support from the National Institutes of Health (NIH) Maximizing Access to Research Careers (MARC) U*STAR Program (NIH T34-GM008612-20) and the Louis Stokes Alliance for Minority Participation (NSF HRD-0802628) research fellowship.

Funding

This work was funded by grants to MPC from the NIH AREA R15-NS070774-01, NIH MARC U*STAR Program T34-GM008612-20, National Science Foundation MCB-0920127, and Cal State Fullerton Intramural Grants program.

Conflict of interest

The authors declare no conflict of interest concerning this work.

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Authors and Affiliations

  1. Department of Biological Science, California State University Fullerton, 800 N. State College Blvd., Fullerton, CA, 92831, USA

    Math P. Cuajungco, Joshua Silva, Ania Habibi & Jessica A. Valadez

  2. Center for Applied Biotechnology Studies, California State University Fullerton, Fullerton, CA, 92831, USA

    Math P. Cuajungco

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  1. Math P. Cuajungco
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  2. Joshua Silva
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Correspondence to Math P. Cuajungco.

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Cuajungco, M.P., Silva, J., Habibi, A. et al. The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function. Pflugers Arch - Eur J Physiol 468, 177–192 (2016). https://doi.org/10.1007/s00424-015-1732-2

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