Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS

Abstract

Glutamatergic neurotransmission entails a tonic loss of glutamate from nerve endings into the synapse. Replacement of neuronal glutamate is essential in order to avoid depletion of the internal pool. In brain this occurs primarily via the glutamate-glutamine cycle, which invokes astrocytic synthesis of glutamine and hydrolysis of this amino acid via neuronal phosphate-dependent glutaminase. This cycle maintains constancy of internal pools, but it does not provide a mechanism for inevitable losses of glutamate N from brain. Import of glutamine or glutamate from blood does not occur to any appreciable extent. However, the branched-chain amino acids (BCAA) cross the blood-brain barrier swiftly. The brain possesses abundant branched-chain amino acid transaminase activity which replenishes brain glutamate and also generates branched-chain ketoacids. It seems probable that the branched-chain amino acids and ketoacids participate in a "glutamate-BCAA cycle" which involves shuttling of branched-chain amino acids and ketoacids between astrocytes and neurons. This mechanism not only supports the synthesis of glutamate, it also may constitute a mechanism by which high (and potentially toxic) concentrations of glutamate can be avoided by the re-amination of branched-chain ketoacids.

Keywords: Brain; Brain metabolism; Branched-chain amino acids; Glutamate; Metabolism.

Figure 1

Proposed schematic of glutamate-BCAA cycle. Leucine illustrated to typify metabolism of isoleucine and valine. Leucine enters brain in exchange for glutamine, formed in astrocytes. In the astrocyte mitochondrial branched-chain transaminase (BCATm) forms glutamate and α-ketoisocaproate (KIC), the cognate ketoacid. The latter is transferred from astrocyte to neuron, which reaminates KIC via cytosolic branched-chain amino acid transaminase (BCATc), in the process consuming glutamate. The leucine so formed is restored to astrocytes, thereby completing the cycle.