- Glutamine, glutamate and GABA
- Glutamate/GABA-glutamine cycle
- Transporter proteins
- Role of glutamine in maintaining blood pH
The chemical structures of a) glutamine, b) glutamate, and c) GABA.
Glutamine (Gln) is the most abundant free amino acid in plasma, cerebrospinal fluid and brain extracellular space. Though it is produced mainly by liver, muscle and astroglial cells, it is consumed by a variety of cell types, including neurons, liver, kidney and activated immune cells, as well as other rapidly dividing cells (e.g., intestinal, hair, and tumor cells).
The biological roles of Glutamine are diverse. For instance, Glutamine is crucial to central metabolism, acting as a carbon doner to the citric acid cycle and a nitrogen donor for other anabolic processes, such as the formation of amino acids, amino sugars, purines and pyrimidines. Glutamine is also involved in the detoxification and transport of ammonia, and plays an important role in maintaining blood pH (more detailed information below). Finally, glutamine is a precursor compound for production of glutamate and GABA; the most important excitatory and inhibitory neurotransmitters in the brain, respectively.
Glutamate (Glu; glutamic acid) is a non-essential amino acid. Although structurally similar to glutamine, with a hydroxy group in place of an amide, glutamate has different biological roles. Glutamate is the most abundant excitatory neurotransmitter in the brain, with a role in long-term potentiation, and is important for learning and memory.; a characteristic that is particularly relevant to the Chaudhry group. In terms of cellular metabolism, for example, glutamate is involved in transamination and deamination reactions and facilitates the excretion of nitrogen in the urin.
GABA (gamma-Aminobutyric acid) is the most important inhibitory neurotransmitter in the brain.
The neurotransmitters glutamate and GABA are stored in vesicles in the presynaptic nerve terminal. The fusion of the vesicle membrane with the plasma membrane is triggered by a nervous impulse, releasing the neurotransmitters into the synaptic cleft. Glutamate and GABA then ligate with their corresponding receptors on the post-synaptic neuron, transmitting excitatory or inhibitory signals, respectively.
After release, the excess glutamate and GABA must be rapidly removed from the synapse in order to avoid inappropriate signal transduction. A build up of excess glutamate in the synaptic cleft can lead to neuronal damage and eventually cell death (known as excitotoxicity). When taken up by neurons, glutamate is repackaged into vesicles and can be reused in signal transduction. Uptake into glia, however, invovles more steps before the neurotransmitters can be recycled; glutamate is first converted to glutamine, then released from the glia to be transported into the pre-synaptic neuron, where it is converted back to glutamate (or further to GABA in inhibitory neurons), and stored in vesicles ready for the next nervous impulse. This cycle is known as the glutamate/GABA-glutamine cycle. The transport of these neurotransmitters and intermediates takes place against concentration gradients and thus requires the action of transporter proteins.
Transporter proteins are integral membrane proteins that are characterised by their ability to mediate the transmembrane movement of small hydrophilic molecules against concentration gradients. Transporters located in the plasma membrane actively transport molecules across the membrane, energized mainly via the co-transport of Na+ as it moves down its electrochemical gradient. Transporters located in synaptic vesicles, however, are Na+-independent; driven by the electrical and/or chemical H+ gradient, these transporters facilitate the intravesicular accumulation of neurotransmitters at high concentrations prior to their release.
The Chaudhry Group is focused on several membrane transporters in the Slc38 family, including the System A Transporters SAT1 (Slc38A1) and SAT2 (Slc38A2) and the System N transporter SN1 (Slc38A3). SN1 is the transporter that releases glutamine from glia cells, whereas both SAT1 and SAT2 transport glutamine into neurons against a concentration gradient. SN1 is also expressed in the kidney, and both its localisation to the basolateral membranes of tubule cells and the presence of a putative pH responsive element in the 3' untranslated region are conducive to its function in pH regulation.
The pH of blood must be maintained at 7.4, with very little tolerance for either increase or decrease; acidosis manifests when pH falls below 7.35, and alkalosis when pH rises above 7.45.
Glutamine degradation in kidney leads to the formation of NH4+ (ammonium) and HCO3- (bicarbonate) ions. Ammonium is excreted in the preurine, whereas bicarbonate is trasnported to the peritubular blood and back into general circulation, where it acts as a buffer for regulating pH.