High-affinity, Na+-dependent synaptosomal amino acid uptake systems are strongly stimulated by proteins which are known to bind free fatty acids. The rate of uptake as well as the overall level of accumulation is increased by such proteins as bovine serum albumin, hepatic fatty acid binding protein, beta-lactoglobulin, and fetuin. Such a stimulation is not observed with proteins which do not bind fatty acids. The transport activity of synaptosomal preparations can be directly correlated with the free fatty acid content of the preparation. Thus, incubation with albumin reduces the free fatty acid content of synaptosomal preparations, suggesting that the stimulatory effects of the proteins are related to their removal of inhibitory fatty acids formed by hydrolysis of membrane lipids during incubation. Inhibition of amino acid uptake is seen with most cis-unsaturated long chain fatty acids while saturated and trans-unsaturated fatty acids have relatively little or no effect. Under conditions in which the ionophore gramicidin D causes an increase of 22Na flux into synaptosomes, oleic acid (50 microM) has no effect on the influx. These data are consistent with the hypothesis proposed earlier by us [Rhoads, D. E., Peterson, N. A., & Raghupathy, E. (1982) Biochemistry 21, 4782] that Na+-dependent amino acid transport carrier proteins reside in a relatively fluid lipid domain in the synaptosomal membrane and that the effects of cis-unsaturated fatty acids are mediated by interactions with such domains.

Evidence is presented which suggests that proline, pipecolic acid, and glycine are accumulated by a common transport system in rat brain cortical synaptosomes and synaptosomal plasma membrane vesicles. This system is Na+ dependent and appears to be similar to the iminoglycine transport system present in renal tubules and in renal brush border membranes. The opioid pentapeptides Leu- and Met-enkephalin specifically inhibit the uptake of these three imino/amino acids, presumably by interaction with a nonopioid receptor, since the inhibition is not affected by the opiate antagonist naloxone and occurs with des-tyrosyl enkephalins as well as with the intact pentapeptides.