Human organic anion transporter 1 (hOAT1) plays a critical role in the body disposition of environmental toxins and clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. We have demonstrated previously that hOAT1 forms homo-oligomers in cultured cells and in rat kidney. However, the functional consequence of such oligomerization has never been elucidated. In the current study, we used a novel approach by examining the effects of short hydrophobic peptides corresponding to transmembrane domains (TMDs) 1 to 12 of hOAT1 on the oligomerization and function of the transporter. We constructed expression vectors encoding short fusion peptides corresponding to TMDs 1 to 12 of hOAT1. These peptides were transfected into hOAT1-expressing COS-7 cells. Our results showed that among all 12 peptides examined, only the peptide corresponding to TMD 6 of hOAT1 significantly disrupted hOAT1 oligomerization demonstrated by cross-linking and coimmunoprecipitation experiments. The same peptide also caused a reduced expression of hOAT1 at the cell surface. As a result, hOAT1-mediated transport activity was compromised. Our data suggest that the peptide corresponding to TMD 6 of hOAT1 is a potent inhibitor of hOAT1 oligomerization and that oligomerization of hOAT1 is critical for the expression of the transporter at the cell surface and consequently for the proper function of the transporter
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