The basic objective of this research is to define the mechanism(s) of inhibition of Na+ dependent, neuroactive amino acid transport by unsaturated free fatty acids and to determine a physiological role for such inhibition. Our experiments lead us to conclude that unsaturated free fatty acids can act as selective modulators of neurotransmitter amino acid transport and that this effect is related to their effect on lipid-lipid or lipid-protein interaction in synaptosomal membranes. Thus, the actions of free fatty acids that we have shown in our transport studies may indeed be significant to the normal permeability characteristics of synaptic membranes. Such considerations are in line with recent evidence that permeability properties of membranes and a variety of protein-mediated membrane activities can be markedly influenced by the fatty acid composition of the phospholipids and in particular by their degree of unsaturation. The present grant will attempt i) to elucidate the mechanisms of action of unsaturated free fatty acids on synaptosomal neurotransmitter amino acid transport, ii) to provide further evidence that these fatty acids act as endogenous modulators of transport, iii) to explore the in vivo significance of these findings or in other words, to study neurotransmitter amino acid transport activity under in vivo conditions in which unsaturated free (and perhaps esterified as well) fatty acid levels are altered, iv) to search for low molecular weight, fatty acid binding proteins (12,000d) in cerebral tissue similar to the ones found in nonneuronal tissues which in turn can regulate the availability of free fatty acids to synaptic membranes and to measure the membrane potentials under these various in vitro and in vivo conditions. Finally, our observation that insulin strongly stimulates neurotransmitter amino acid transport in synaptic preparations is consistent with the observed effects of fatty acids on transport. Evidence will be sought to demonstrate the existence of hormone-sensitive lipase(s) in brain and to establish possible roles for these enzymes in neurotransmitter amino acid transport.
| Sankaran, H; Wong, A; Khan, S J et al. (1987) Bioassayable cholecystokinin in the brain of the goldfish, Carassius auratus. Neuropeptides 9:103-11 |
| Rhoads, D E; Sankaran, H; Peterson, N A et al. (1986) Interaction of enkephalins and des-tyrosyl-enkephalins with synaptosomal plasma membrane vesicles: enkephalin binding and inhibition of proline transport. Biochemistry 25:1580-4 |
