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Turning On TRPM3

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Science Signaling  09 Dec 2008:
Vol. 1, Issue 49, pp. ec419
DOI: 10.1126/scisignal.149ec419

Members of the transient receptor potential (TRP) family of cation channels are activated by diverse stimuli to serve various functions (see Nilius and Voets). Noting that TRPM3 is found in brain, Wagner et al. screened brain messenger molecules for the ability to elicit calcium signals in HEK (human embryonic kidney) 293 cells expressing a calcium-permeable TRPM3 splice variant and identified the neurosteroid pregnenolone sulphate (PS) as a ligand. PS rapidly (within 100 ms) and robustly activated TRPM3 but did not activate other TRP channels tested; patch-clamp analysis indicated that it acted extracellularly and that PS-dependent TRPM3 current was inhibited by monovalent cations. PS-elicited calcium currents with a biophysical and pharmacological profile like that of TRPM3 (activated by nifedipene as well as by PS) were identified in cultured mouse pancreatic islet cells and a rat pancreatic β cell line (Ins1). Moreover, reverse transcription polymerase chain reaction (RT-PCR) and Northern analysis confirmed the presence of trpm3 transcripts in Ins1 and islet cells, and TRPM3 knockdown decreased PS-induced calcium signals in Ins1 cells. By combining calcium imaging with immunohistochemical analysis, the authors determined that PS-activated calcium channels were present in insulin-producing pancreatic β cells, but not glucagon-producing α cells, and that PS elicited calcium signals in islet cells. Indeed, PS potentiated glucose-dependent insulin secretion from pancreatic islets (an effect apparent at supraphysiological concentrations). Thus, PS acts as an endogenous ligand for TRPM3, an effect that may prove therapeutically useful, although its physiological relevance remains to be determined.

T. F. J. Wagner, S. Loch, S. Lambert, I. Straub, S. Mannebach, I. Mathar, M. Düfer, A. Lis, V. Flockerzi, S.E. Philipp, J. Oberwinkler, Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic β cells. Nat. Cell Biol. 10, 1421–1430 (2008). [PubMed]

B. Nilius, T. Voets, A TRP channel-steroid marriage. Nat. Cell Biol. 10, 1383-1384 (2008). [PubMed]

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