The neurotransmitter is formed from glutamate by the action of glutamate decarboxylase. It appears that glutamine serves as the precursor for glutamate, making phosphate-activated glutaminase, an important enzyme for synthesis.
It took a long time to realize that glutamate is a neurotransmitter
It may sound astonishing, but it took the scientific community a long time to realize that glutamate is a neurotransmitter although it was noted already 70 years ago that glutamate is abundant in the brain and that it plays a central role in brain metabolism. Ironically, the reason for the delay seems to have been its overwhelming importance. Brain tissue contains as much as 5 - 15 mmol glutamate pr kg, depending on the region, more than of any other amino acid. Glutamate is one of the ordinary 20 amino acids which are used to make proteins and takes parts in typical metabolic functions like energy production and ammonia detoxification in addition to protein synthesis. It was hard to believe that a compound with so many functions and which is present virtually everywhere in high concentrations could play an additional role as transmitter.
As shown in , ACh is synthesized by choline acetyltransferase (ChAT), and is loaded into synaptic vesicles by the vesicular acetylcholine transporter (VAChT). The synaptic vesicle lumen is acidified by the action of an ATP-dependent proton pump located in the synaptic vesicle membrane. The pH gradient between the vesicle lumen and the cytoplasm provides the driving force for ACh transport; the VAChT essentially “exchanges” ACh for protons. The docking and priming of synaptic vesicles, and their calcium-stimulated fusion with the cell membrane are all general processes that are independent of the neurotransmitter contained in the vesicles (and are described elsewhere in this volume). Following synaptic vesicle fusion and transmitter release, the ACh diffuses within the synaptic cleft and activates acetylcholine receptors (AChRs), usually located on post-synaptic cells. For most other neurotransmitters (e.g., GABA, dopamine, serotonin), the action of the transmitter is terminated by transporter- mediated removal of the transmitter from the synaptic cleft. The action of acetylcholine, however, is terminated by direct enzymatic hydrolysis of the neurotransmitter in the synaptic cleft by acetylcholinesterase (AChE). The resulting choline is then transported back into the presynaptic neuron by a high affinity choline transporter (HAChT, or ChT); this choline is then available for the synthesis of additional ACh.
Genetic and molecular studies showed that and were part of a complex gene locus and transcription unit, with the gene nested in the long first intron of (see ; ; ). Thus, the sequential steps of acetylcholine synthesis and vesicle-loading are encoded by different genes within a single, complex transcription unit. Subsequent studies demonstrated that a similar nested structure of these genes is present in mammals and insects (; ). This is now commonly called the cholinergic gene locus, or CGL, and is present in all metazoans thus far examined (). It is noteworthy that the genes encoding enzymes and transporters for other neurotransmitters are not organized in a comparable way.