Small Molecule Activators of TRPML3

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

Research output: Contribution to journalArticle

60 Citations (Scopus)

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

Fingerprint

Chemical activation
Molecules
Melanocytes
Pigmentation
Deafness
Cell membranes
Ion Channels
Scaffolds
Blood Proteins
Membrane Proteins
Cells
Throughput
Cell Membrane
Defects
Testing
Proteins

Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

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

Cite this

Grimm, C., Jörs, S., Saldanha, S. A., Obukhov, A., Pan, B., Oshima, K., ... 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

Small Molecule Activators of TRPML3. / Grimm, Christian; Jörs, Simone; Saldanha, S. Adrian; Obukhov, Alexander; Pan, Bifeng; Oshima, Kazuo; Cuajungco, Math P.; Chase, Peter; Hodder, Peter; Heller, Stefan.

In: Chemistry and Biology, Vol. 17, No. 2, 26.02.2010, p. 135-148.

Research output: Contribution to journalArticle

Grimm, C, Jörs, S, Saldanha, SA, Obukhov, A, Pan, B, Oshima, K, Cuajungco, MP, Chase, P, Hodder, P & Heller, S 2010, 'Small Molecule Activators of TRPML3', Chemistry and Biology, vol. 17, no. 2, pp. 135-148. https://doi.org/10.1016/j.chembiol.2009.12.016
Grimm C, Jörs S, Saldanha SA, Obukhov A, Pan B, Oshima K et al. Small Molecule Activators of TRPML3. Chemistry and Biology. 2010 Feb 26;17(2):135-148. https://doi.org/10.1016/j.chembiol.2009.12.016
Grimm, Christian ; Jörs, Simone ; Saldanha, S. Adrian ; Obukhov, Alexander ; Pan, Bifeng ; Oshima, Kazuo ; Cuajungco, Math P. ; Chase, Peter ; Hodder, Peter ; Heller, Stefan. / Small Molecule Activators of TRPML3. In: Chemistry and Biology. 2010 ; Vol. 17, No. 2. pp. 135-148.
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