|Budget Amount *help
¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 1999 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
The major component of the blood-brain barrier is the tightly sealed brain capillary endothelial cells which form a permeation barrier for hydrophilic compounds. To provide brain tissues with essential nutrients such as sugars and amino acids, the blood-brain barrier is, thus, equipped with specialized transport systems. The amino acid transport systems are also important as a permeation path for amino acid-related drugs. Blood-brain barrier possesses transport systems for organic anions. This system is proposed to be essential to extrude monoamine metabolites and conjugated compounds formed in the brain tissues. The purpose of this study is to identify molecular nature of the transport systems for organic anions and amino acids.
Based on the sequence homology to the organic anion transporter OAT1, we identified novel organic anion transporters OAT2, OAT3 and OAT4 and established an organic anion transporter family. OAT1 was present in astrocyte processes surrounding capillaries. OAT1 is, thus, proposed to mediate the transfer of organic anions from astrocytes to capillary endothelial cells, which is critical for the excretion of anionic metabolites produced in neurones. OAT3 accepts conjugated compounds as its substrates. It would, therefore, be suitable as an organic anion transporting system in the blood-brain barrier.
We identified system L transporters, LAT1 and LAT2, which associate with single membrane spanning protein, 4F2hc. We further found transporters related LAT1 and established the heterodimeric amino acid transporter family. By gencrating specific antibodies against LAT1, LAT2 and 4F2hc, we showed that these proteins exist on the brain capillary endothelial cells. These proteins were found to be present in the luminal and abluminal membranes. Thus, both LAT1 and LAT2 are proposed to play critical roles in the permeation of amino acids and amino acid related drugs through the blood-brain barrier.