Characterization of the uptake of GABA, nipecotic acid and cis-4-OH-nipecotic acid in cultured neurons and astrocytes.

The transport kinetics of GABA, (RS)-nipecotic acid and (3RS, 4SR)-4-hydroxynipecotic acid and the mutual inhibition patterns of these compounds were investigated in cultured cerebral cortex neurons and astrocytes together with the inhibitory patterns of other GABA analogues with regard to inhibition of GABA transport. (R)-4-Methyl-GABA, (R)-4-methyl-trans-4-aminocrotonic acid, guvacine, (R)-nipecotic acid and N-methyl-nipecotic acid were found to inhibit GABA uptake into neurons and astrocytes in a competitive manner. On the other hand, (3RS, 4SR)-4-hydroxynipecotic acid was shown to be a non-competitive inhibitor of astroglial GABA uptake but a competitive inhibitor of neuronal GABA uptake. Accordingly, GABA was found to inhibit (3RS, 4SR)-4-hydroxynipecotic acid uptake in a complex manner in astrocytes whereas it inhibited neuronal uptake of (3RS, 4SR)-4-hydroxynipecotic acid in a competitive manner. GABA as well as the two analogues were transported with high affinity in both neurons and astrocytes. Altogether, the results confirm the notion that GABA transport carriers in neurons and astrocytes have distinctly different requirements for the conformation of the GABA molecule. Moreover, they also suggest that heterogeneity of the GABA carrier may be found within each of the cell types.