The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1
- 10 September 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Pflügers Archiv - European Journal of Physiology
- Vol. 459 (1), 79-91
- https://doi.org/10.1007/s00424-009-0716-5
Abstract
Mucolipidosis type IV is a lysosomal storage disorder caused by the loss or dysfunction of the mucolipin-1 (TRPML1) protein. It has been suggested that TRPML2 could genetically compensate (i.e., become upregulated) for the loss of TRPML1. We thus investigated this possibility by first studying the expression pattern of mouse TRPML2 and its basic channel properties using the varitint-waddler (Va) model. Here, we confirmed the presence of long variant TRPML2 (TRPML2lv) and short variant (TRPML2sv) isoforms. We showed for the first time that, heterologously expressed, TRPML2lv-Va is an active, inwardly rectifying channel. Secondly, we quantitatively measured TRPML2 and TRPML3 mRNA expressions in TRPML1–/– null and wild-type (Wt) mice. In wild-type mice, the TRPML2lv transcripts were very low while TRPML2sv and TRPML3 transcripts have predominant expressions in lymphoid and kidney organs. Significant reductions of TRPML2sv, but not TRPML2lv or TRPML3 transcripts, were observed in lymphoid and kidney organs of TRPML1–/– mice. RNA interference of endogenous human TRPML1 in HEK-293 cells produced a comparable decrease of human TRPML2 transcript levels that can be restored by overexpression of human TRPML1. Conversely, significant upregulation of TRPML2sv transcripts was observed when primary mouse lymphoid cells were treated with nicotinic acid adenine dinucleotide phosphate, or N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline sulfonamide, both known activators of TRPML1. In conclusion, our results indicate that TRPML2 is unlikely to compensate for the loss of TRPML1 in lymphoid or kidney organs and that TRPML1 appears to play a novel role in the tissue-specific transcriptional regulation of TRPML2.Keywords
This publication has 66 references indexed in Scilit:
- Activating Mutations of the TRPML1 Channel Revealed by Proline-scanning MutagenesisOnline Journal of Public Health Informatics, 2009
- The two-pore channel TPCN2 mediates NAADP-dependent Ca2+-release from lysosomal storesPflügers Archiv - European Journal of Physiology, 2009
- NAADP mobilizes calcium from acidic organelles through two-pore channelsNature, 2009
- Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophilsCell Calcium, 2008
- A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotypeThe EMBO Journal, 2008
- Formation of a new receptor‐operated channel by heteromeric assembly of TRPP2 and TRPC1 subunitsEMBO Reports, 2008
- The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degenerationProceedings of the National Academy of Sciences of the United States of America, 2008
- A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouseProceedings of the National Academy of Sciences of the United States of America, 2007
- Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint–waddler miceProceedings of the National Academy of Sciences of the United States of America, 2007
- Defective B cell development and function in Btk-deficient miceImmunity, 1995