Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected].
TRPM3, a member of the melastatin-like transient receptor potential channel subfamily (TRPM), is predominantly expressed in human kidney and brain. TRPM3 mediates spontaneous Ca2+ entry and nonselective cation currents in transiently transfected human embryonic kidney 293 cells. Using measurements with the Ca2+-sensitive fluorescent dye fura-2 and the whole-cell patch-clamp technique, we found that D-erythro-sphingosine, a metabolite arising during the de novo synthesis of cellular sphingolipids, activated TRPM3. Other transient receptor potential (TRP) channels tested [classic or canonical TRP (TRPC3, TRPC4, TRPC5), vanilloid-like TRP (TRPV4, TRPV5, TRPV6), and melastatin-like TRP (TRPM2)] did not significantly respond to application of sphingosine. Sphingosine-induced TRPM3 activation was not mediated by inhibition of protein kinase C, depletion of intracellular Ca2+ stores, and intracellular conversion of sphingosine to sphingosine-1-phosphate. Although sphingosine-1-phosphate and ceramides had no effect, two structural analogs of sphingosine, dihydro-D-erythro-sphingosine and N,N-dimethyl-D-erythro-sphingosine, also activated TRPM3. Sphingolipids, including sphingosine, are known to have inhibitory effects on a variety of ion channels. Thus, TRPM3 is the first ion channel activated by sphingolipids.
Grimm
Christian
C
Institut für Pharmakologie, Charité Campus Benjamin Franklin, Thielallee 69-73, 14195 Berlin, Germany.
Kraft
Robert
R
Schultz
Günter
G
Harteneck
Christian
C
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007668:Kidney; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000378:metabolism; D013107:Sphingolipids / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050053:TRPM Cation Channels; D014162:Transfection
D007473:Ion Channels; D011994:Recombinant Proteins; D013107:Sphingolipids; D050053:TRPM Cation Channels; C475667:TRPM3 protein, human; C481931:erythro-(2R,3S)-sphingosine; D013110:Sphingosine; D002118:Calcium