while the complementary strand 3 was unchanged (Scheme 1).

The emergence of superoxide anion radicals (O2-) in the guinea pig inner ear following acoustic trauma was investigated by histochemical methods. Five minutes after exposure to sound at 120-125 dB SPL for 3 h, an O2- reaction product was detected in the cochlea along the luminal membrane of the marginal cells of the stria vascularis. This reaction product could not be found at 30 min, but reappeared at 2 h. The first appearance of O2- is not explainable by our studies, but the second appearance may be related to recirculation of strial blood flow after blood flow stasis. The present observations raise the possibility that free radicals are produced in the inner ear after acoustic trauma and lead to inner ear damage.

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We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation. Importantly, we show that a characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+-signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase.