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We have investigated the role of NAADP-mediated Ca2+ mobilization in endothelin (ET) signaling via endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB) in rat peritubular smooth muscle cells. Microinjection and extracellular application of NAADP were both able to elicit Ca2+ release which was blocked by inhibitory concentrations of NAADP, by impairing Ca2+ uptake in acidic stores with bafilomycin, and by thapsigargin. Ca2+ release in response to selective ETB stimulation was abolished by inhibition of NAADP signaling through the same strategies, while these treatments only partially impaired ETA-dependent Ca2+ signaling, showing that transduction of the ETB signal is dependent on NAADP. In addition, we show that lipid rafts/caveolae contain ETA, ETB, and NAADP/cADPR generating enzyme CD38 and that stimulation of ETB receptors results in increased CD38 activity; interestingly, ETB- (but not ETA-) mediated Ca2+ responses were antagonized by disruption of lipid rafts/caveolae with methyl-β-cyclodextrin. These data demonstrate a primary role of NAADP in ETB-mediated Ca2+ signaling and strongly suggest a novel role of lipid rafts/caveolae in triggering ET-induced NAADP signaling. J. Cell. Physiol. 216: 396–404, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]