The glutamine commute: take the N line and transfer to the A

Abstract

The transfer of glutamine between cells contributes to signaling as well as to metabolism. The recent identification and characterization of the system N and A family of transporters has begun to suggest mechanisms for the directional transfer of glutamine, and should provide ways to test its physiological significance in diverse processes from nitrogen to neurotransmitter release.

Figure 1.

The glutamine–glutamate cycles in the liver and nervous system. (A) In periportal cells (top) of the liver, glutaminase (glnase) converts glutamine to glutamate and ammonia. Along with the ammonia directly supplied from the portal circulation, the ammonia derived from glutamine feeds into the urea cycle. The glutamine synthetase (gs) in perivenous cells (bottom) converts the ammonia that escapes the urea cycle into glutamine. (B) In the nervous system, the glutamate released by exocytosis from nerve terminals is taken up by astrocytes through known excitatory amino acid transporters and converted to glutamine by glutamine synthetase. Glutamine is then transferred from astrocytes to neurons and converted back to glutamate by glutaminase before packaging into vesicles.

Figure 2.

Ionic coupling of VGAT, system N, and system A transporters. VGAT (left) couples the uptake of GABA by synaptic vesicles to the movement of H⁺ down their electrochemical gradient (out of vesicles). The positive charge inside synaptic vesicles contributes to the driving force on H⁺. System N transporters (middle) mediate the Na⁺-dependent uptake of glutamine in exchange for H⁺. Electroneutrality appears to contribute to the shallow amino acid gradients achieved. In contrast, system A transporters (right) mediate only Na⁺ cotransport with amino acid. Since amino acid substrates are generally neutral, transport is electrogenic, and the resting membrane potential contributes to the driving force on Na⁺, predicting the accumulation of amino acid to high concentrations.