Glutamate and Its Derivatives in Regulation of Peripheral Cholinergic Neurotransmission

Glutamate is the master excitatory neurotransmitter in the central nervous system, while gamma-aminobutyric acid (GABA), produced due to glutamate decarboxylation, functions as the master inhibitory neurotransmitter. N-acetylaspartylglutamate (NAAG), the most abundant neuropeptide in the CNS, is also capable of acting as a neurotransmitter. This review addresses experimental data that prove the involvement of all these three signaling molecules in the functioning of a neuromuscular junction, a classical cholinergic synapse in the peripheral nervous system that has been considered to be the most studied in the organism of vertebrates and humans until recently. To date, all three signaling molecules have been found at the neuromuscular junction and shown to release into the synaptic cleft. Moreover, there have been identified receptor proteins whose activation influences both spontaneous and evoked quantal acetylcholine release. Notably, glutamate, NAAG and GABA inhibit non-quantal acetylcholine release in mammalian synapses. The mechanisms of these modulatory signaling pathways of glutamate and its derivatives are implemented due to cooperation of all three compartments of the neuromuscular junction: nerve ending, muscle fiber, and perisynaptic Schwann cell.