Small molecule activators of TRPML3.
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.
Grimm
Christian
C
Departments of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jörs
Simone
S
Saldanha
S Adrian
SA
Obukhov
Alexander G
AG
Pan
Bifeng
B
Oshima
Kazuo
K
Cuajungco
Math P
MP
Chase
Peter
P
Hodder
Peter
P
Heller
Stefan
S
D002460:Cell Line; D004705:Endocytosis; D006198:Hair Cells, Auditory / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008544:Melanocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000819:agonists* / Q000378:metabolism
C510642:MCOLN3 protein, human; D054852:Small Molecule Libraries; D050051:Transient Receptor Potential Channels; D012964:Sodium