The transporter regulator RS1 was identified as an IRIP-interacting protein in yeast two-hybrid screening. The interaction between IRIP and RS1 was further confirmed in coimmunoprecipitation assays. A possible role of IRIP in regulating transporter activity was subsequently investigated. IRIP overexpression inhibited endogenous 1-methyl-4-phenylpyridinium (MPP +) uptake activity in HeLa cells. The activities of exogenous organic cation transporters (OCT2 and OCT3), organic anion transporter (OAT1), and monoamine transporters were also inhibited by IRIP. Conversely, inhibition of IRIP expression by small interfering RNA or antisense RNA increased MPP + uptake. We measured transport kinetics of OCT2-mediated uptake and demonstrated that IRIP overexpression significantly decreased V max but did not affect K m. On the basis of these results, we propose that IRIP regulates the activity of a variety of transporters under normal and pathological conditions. Ischemia/reperfusion (I/R) is the major cause of tissue injury under many pathophysiological conditions such as stroke, myocardial infarction, and acute renal failure ( 1, 11). Similar to other stress conditions, I/R causes dramatic changes in cell physiology and metabolism. Ischemic tissue is deprived of oxygen and essential substrates for energy metabolism. As the cellular oxygen is depleted, mitochondrial oxidative phosphorylation and ATP production rates decrease. There are several important consequences of ATP depletion.
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