Small Molecule Activators of TRPML3

Christian Grimm, Simone Jörs, S. Adrian Saldanha, Alexander G. Obukhov, Bifeng Pan, Kazuo Oshima, Math P. Cuajungco, Peter Chase, Peter Hodder, Stefan Heller

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)135-148
Number of pages14
JournalChemistry and Biology
Volume17
Issue number2
DOIs
StatePublished - Feb 26 2010

Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Small Molecule Activators of TRPML3'. Together they form a unique fingerprint.

  • Cite this

    Grimm, C., Jörs, S., Saldanha, S. A., Obukhov, A. G., Pan, B., Oshima, K., Cuajungco, M. P., Chase, P., Hodder, P., & Heller, S. (2010). Small Molecule Activators of TRPML3. Chemistry and Biology, 17(2), 135-148. https://doi.org/10.1016/j.chembiol.2009.12.016