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PMID: 20189104 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Small molecule activators of TRPML3.

Chemistry & biology ·Vol. 17 ·No. 2 ·2010-02-26 ·Pages 135-48

Grimm C, Jörs S, Saldanha SA, Obukhov AG, Pan B, Oshima K, Cuajungco MP, Chase P, Hodder P, Heller S

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.

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,pharmacology Sodium/metabolism Transient Receptor Potential Channels/agonists,metabolism
Chemicals
MCOLN3 protein, human Small Molecule Libraries Transient Receptor Potential Channels Sodium
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Grimm Christian
Departments of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jörs Simone
Saldanha S Adrian
Obukhov Alexander G
Pan Bifeng
Oshima Kazuo
Cuajungco Math P
Chase Peter
Hodder Peter
Heller Stefan
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Article Info
Journal
Chemistry & biology
Abbr.
Chem Biol
ISSN
1879-1301
DOI
10.1016/j.chembiol.2009.12.016
Published
2010-02-26
Pages
135-48
Language
English
Region
United States
NLM ID
9500160
PMCID
PMC2834294
Subset
IM
Grants
NIDCD NIH HHS · R01 DC004563-07A1 · United States
NIDCD NIH HHS · P30 DC010363-017736 · United States
NIMH NIH HHS · U54 MH084512 · United States
NIMH NIH HHS · U54 MH084512-010010 · United States
NIMH NIH HHS · U54 MH084512-02 · United States
NIDCD NIH HHS · DC004563 · United States
NIDCD NIH HHS · P30 DC010363-01 · United States
NIMH NIH HHS · MH083077 · United States
NIDCD NIH HHS · P30 DC010363 · United States
NIMH NIH HHS · U54MH084512 · United States
NIMH NIH HHS · R03 MH083077 · United States
NIMH NIH HHS · R03 MH083077-01 · United States
NIDCD NIH HHS · R01 DC004563 · United States
NIMH NIH HHS · U54 MH084512-020010 · United States
NIMH NIH HHS · U54 MH084512-01 · United States
NIDCD NIH HHS · R01 DC004563-08 · United States
NIDCD NIH HHS · P30 DC010363-017737 · United States
NIDCD NIH HHS · R01 DC004563-09 · United States
NIDCD NIH HHS · P30 DC010363-017735 · United States
Corrections
CommentIn
PMID: 20338511
External Links
PubMed source DOI: 10.1016/j.chembiol.2009.12.016 PMC Full Text
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