Small molecule activators of TRPML3

Chem Biol. 2010 Feb 26;17(2):135-48. doi: 10.1016/j.chembiol.2009.12.016.


We conducted a high-throughput screen for small molecule activators of the TRPML3 ion channel, which, when mutated, causes deafness and pigmentation defects. Cheminformatics analyses of the 53 identified and confirmed compounds revealed nine different chemical scaffolds and 20 singletons. We found that agonists strongly potentiated TRPML3 activation with low extracytosolic [Na(+)]. This synergism revealed the existence of distinct and cooperative activation mechanisms and a wide dynamic range of TRPML3 activity. Testing compounds on TRPML3-expressing sensory hair cells revealed the absence of activator-responsive channels. Epidermal melanocytes showed only weak or no responses to the compounds. These results suggest that TRPML3 in native cells might be absent from the plasma membrane or that the protein is a subunit of heteromeric channels that are nonresponsive to the activators identified in this screen.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Endocytosis
  • Hair Cells, Auditory / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Melanocytes / drug effects
  • Patch-Clamp Techniques
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Sodium / metabolism
  • Transient Receptor Potential Channels / agonists*
  • Transient Receptor Potential Channels / metabolism


  • MCOLN3 protein, human
  • Small Molecule Libraries
  • Transient Receptor Potential Channels
  • Sodium