Amino Acids and Protein

Neurons and glial cells in brain use amino acids to produce proteins. In addition, certain amino acids are used to produce small functional molecules such as neurotransmitters. Does diet influence amino acid flow into brain, and their use in generating proteins and transmitters? The path from diet to brain proceeds from amino acid absorption from the gastrointestinal tract, insertion into the circulation, and extraction by brain. This extraction process involves the BBB, which contains a number of transporters for amino acids. The properties of these transporters dictate how much of each amino acid enters (and exits) the brain. Currently, six carriers have been identified. Of special interest are two carriers: (1) the large neutral amino acid (LNAA) carrier, which is shared by several amino acids (some are precursors for neurotransmitters: phenylalanine, tyrosine, tryptophan, histidine). The carrier is competitive, allowing changes in the plasma concentration of any one LNAA to affect not only that amino acid's BBB transport, but also that of each of its transport competitors. Glutamine, an LNAA present in brain in high concentrations, drives the brain uptake of the other LNAA, by serving as the principal amino acid counter-transported from brain to blood each time an LNAA is taken up into brain; and (2) the acidic amino acid carrier, which transports glutamic and aspartic acids. This carrier primarily transports glutamate and aspartate from the brain to the circulation. The other transporters include one selective for basic amino acids, two selective for subgroups of the small, neutral amino acids, and one selective for taurine.

The carriers that move amino acids into brain are those that transport primarily essential amino acids (the large, neutral, and basic amino acids), while those that move amino acids out of brain are those transporting nonessential amino acids (the acidic and small neutral amino acids). A small, net influx into brain of the essential amino acids no doubt reflects their consumption in brain by biosynthetic and metabolic pathways. The net efflux of the non-essential amino acids, notably aspartate, glutamate, glycine and cysteine may serve to remove from brain amino acids that act directly as excitatory transmitters or cotransmitters. The brain carefully compartmentalizes these amino acids metabolically, because they excite neurons, and a mechanism to remove them from brain may be a component of this com-partmentalization design.

Changes in dietary protein intake have no effect on brain protein synthesis in adults. Indeed, the chronic ingestion of very low levels of dietary protein does not depress brain protein synthesis; brain cells may thus be efficient in retaining and reusing amino acids released during intracellular protein breakdown. In neonatal and infant animals, however, low levels of protein intake are associated with below normal rates of protein synthesis in brain. But, the presumed mechanism of this association, reduced uptake of essential amino acids into brain and abnormally low brain concentrations of these amino acids, has not been proven. Hence, at present, there is no convincing evidence linking dietary protein intake and brain protein synthesis via a limitation of amino acid availability to brain. For neurotransmitters, the evidence of this diet-brain link is more certain, and provides interesting examples of the fundamentally different manner in which the brain uses transport carriers to handle amino acids that are neurotransmitter precursors, and those that are neurotransmitters themselves. Good examples are tryptophan (an LNAA) and glutamate (an acidic amino acid), which have been most extensively studied.

Tryptophan (TRP) is the precursor for the neurotransmitter serotonin (5HT). The TRP concentration in brain rapidly influences the rate of 5HT synthesis: raising brain TRP concentrations increases synthesis, while lowering brain TRP decreases synthesis. Brain TRP uptake and concentrations are directly influenced by the plasma concentrations of TRP and its BBB LNAA transport competitors. The plasma concentrations of TRP and the other LNAA are readily modified by food intake, thereby linking diet to brain 5HT synthesis. Dietary proteins and carbohydrates are the food components that change brain TRP and 5HT: carbohydrate ingestion increases plasma TRP, while lowering the plasma concentrations of its LNAA competitors, causing BBB TRP uptake, brain TRP concentrations, and 5HT synthesis all to increase. The ingestion of a meal containing protein raises plasma concentrations of both TRP and its LNAA competitors. As a consequence, TRP experiences no change in competition for BBB transport (and sometimes a reduction, at highprotein intakes), and brain TRP concentrations and 5HT production do not change (or may decline). Hence, a key feature of the LNAA transporter, its competitive nature, explains the impact of meals containing or lacking protein on the production of a molecule important to normal brain function (5HT).

Chronic dietary effects are also observed. For example, chronic ingestion by rats of diets containing proteins with high ratios of one or more LNAA to TRP cause brain TRP and 5HT concentrations to decline. And, the chronic ingestion of diets low in protein causes the plasma concentrations of all LNAAs to decline (including TRP), and brain TRP and 5HT. In this case, brain TRP falls not because of a change in BBB competition, but simply because the BBB uptake of all LNAA declines with falling plasma concentrations (the transporter becomes unsaturated, eliminating competition).

Other LNAA are neurotransmitter precursors in substrate driven pathways in brain. Phenylalanine and tyrosine are substrates for catecholamine synthesis, and histidine is the precursor of histamine. Like TRP, the brain concentrations of these amino acids are influenced by their competitive BBB uptakes from the circulation, and thus the diet.

The nonessential amino acid glutamate (GLU) is an excitatory neurotransmitter, causing neurons that express GLU receptors to depolarize. Because GLU is excitatory, responsive neurons can become overexcited, when subjected to prolonged GLU exposure, and die. The term "excitotoxicity" was coined to describe this effect, and led to the concern that GLU ingested in food (as a constituent of dietary proteins; as a flavoring agent) might cause the brain to become flooded with GLU, causing widespread neurotoxicity. The BBB acidic amino acid transporter prevents this from occurring: it primarily transports GLU out of, not into the brain. Consequently, the BBB functions as a 'barrier' to GLU penetration from the blood.

Another mechanism also protects brain neurons from excessive exposure to GLU. Glial cells rapidly remove GLU from brain extracellular fluid and convert it to an electrically inert amino acid, glutamine. While glial cells efficiently absorb neuronal GLU, they can just as readily clear any GLU that strays into the brain from the circulation.

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