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Identification of Selective Agonists of the Transient Receptor Potential Channels 3 (TRPML3).


Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2012 Mar 21 [updated 2013 Sep 03].

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Lead Identification Division, Translational Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458
Departments of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305.
Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458.


When mutated, the Transient Receptor Potential Channels 3 (TRPML3) ion channel causes deafness and pigmentation defects. Due to the lack of available compounds known to act as selective TRPML3 agonists, the identification of selective probes for TRPML3 are useful to investigate the function of TRPML3 in inner ear mechanotransduction and hearing biology. The two probes reported here, CID 776924 (ML268) and CID 53239838 (ML269), emerged from an HTS-based effort to identify small molecule activators of TRPML3. They exhibit submicromolar EC50 values against TRPML3 in intracellular calcium functional assays. Further, their selectivity & mechanism-of-action has been confirmed in various in patch clamp and functional assays. Interestingly, testing these probes and other TRPML3 activators on TRPML3-expressing sensory hair cells revealed the absence of activator-responsive channels. Similarly, epidermal melanocytes showed only weak or no responses when exposed to the compounds. These studies validate the biological relevance of these probes, as they have now been used to demonstrate that TRPML3 might be absent from the plasma membrane or that the protein is a subunit of heteromeric channels in native cells A comprehensive summary of their activity has been published [1]. ML268 and ML269 are first-in-class tools for elucidating the functions of the TRPML3 ion channel. The significance of their impact was the subject of a special review article [2].

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