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The dopamine precursor L-dihydroxyphenylalanine is transported by the amino acid transporters rBAT and LAT2 in renal cortex

Center of Mineral Metabolism and Clinical Research and Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, and Medical Service, Department of Veterans Affairs Medical Center, Dallas, Texas 75390-8856

Submitted 1 July 2003 ; accepted in final form 8 March 2004

The intrarenal autocrine-paracrine dopamine (DA) system is critical for Na⁺ homeostasis. L-Dihydroxyphenylalanine (L-DOPA) uptake from the glomerular filtrate and plasma provides the substrate for DA generation by the renal proximal tubule. The transporter(s) responsible for proximal tubule L-DOPA uptake has not been characterized. Renal cortical poly-A⁺ RNA injected into Xenopus laevis oocytes induced L-DOPA uptake in a time- and dose-dependent fashion with biphasic K_ms in the millimolar and micromolar range and independent of inward Na⁺, K⁺, or H⁺ gradients, suggesting the presence of low- and high-affinity L-DOPA carriers. Complementary RNA from two amino acid transporters yielded L-DOPA uptake significantly above water-injected controls the rBAT/b^0,+AT dimer (rBAT) and the LAT2/4F2 dimer (LAT2). In contradistinction to renal cortical poly-A⁺, L-DOPA kinetics of rBAT and LAT2 showed classic Michaelis-Menton kinetics with K_ms in the micromolar and millimolar range, respectively. Sequence-specific antisense oligonucleotides to rBAT or LAT2 (AS) caused inhibition of rBAT and LAT2 cRNA-induced L-DOPA transport and cortical poly-A⁺-induced arginine and phenylalanine transport. However, the same ASs only partially blocked poly-A⁺-induced L-DOPA transport. In cultured kidney cells, silencing inhibitory RNA (siRNA) to rBAT significantly inhibited L-DOPA uptake. We conclude that rBAT and LAT2 can mediate apical and basolateral L-DOPA uptake into the proximal tubule, respectively. Additional L-DOPA transport mechanisms exist in the renal cortex that remain to be identified.

sodium balance; amino acid transport; proximal tubule

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