**4. CNS receptors of amino acids**

The neuromediator function of AAs in the CNS is performed through the activation of membrane receptors. After being released from the presynaptic membrane into a synaptic cleft, glutamate and glycine rapidly diffuse to a postsynaptic membrane, where appropriate receptors are further activated.

Glutamate receptors are divided into two groups: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). Excitatory neurotransmission throughout the CNS is mediated by ligand-gated ion channels, including ionotropic glutamate receptors (iGluRs) [33]. Abnormalities in iGluRs lead to a wide range of neurological diseases. Glutamate, the primary neurotransmitter in almost all synapses in the CNS, is released from presynaptic terminals and diffuses to the postsynaptic membrane, where it binds to iGluRs. This process leads to the opening of ion channels, allowing cations to flow in. Thus, the transmembrane channel rapidly depolarizes the postsynaptic membrane. The decrease in membrane potential initiates signal transduction in the postsynaptic neuron. In the iGluR family, four subtypes of integral membrane proteins have been identified in vertebrates based on their pharmacological properties and sequence homologies: α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate (KA), N-methyl-Daspartate (NMDA), and δ-receptors [34]. Subsequent cloning studies have revealed that NMDARs are assembled as heteromers that differ in subunit composition. To date, seven different subunits have been identified and categorized into three subfamilies according to sequence homology [35]. Each iGluR family member exhibits specific kinetic and pharmacological properties in addition to playing a unique role in neurotransmission [36]. The iGluRs are ligand-gated ion channels that are permeable to Na+ and K+ (and Ca2+ in some instances), whereas the mGluRs are G protein-coupled receptors that trigger second messenger cascades. The early component and the late component of neurotransmission are assumed to be mediated by AMPARs and NMDARs/KARs, respectively. This assumption is based on receptor kinetics, as AMPARs are faster and NMDARs/KARs are slower. Nevertheless, acoustic signals are transferred by all of these iGluRs in a precise and reliable manner. Moreover, some auditory processing neurons have a fourth type of iGluR, the delta receptor [34]. The open, or conducting, conformation of the iGluR ion channel is nonselective for monovalent cations. Membrane excitation is often driven by channel permeability to Ca2+. This Ca2+ influx and its physiological and pathological consequences depend strongly on the specific iGluR subtype and the specific subunits in its oligomeric complex [37].

mGluRs are G protein-coupled receptors (GPCRs) that, following activation, regulate both G protein-dependent and G protein-independent signalling pathways. According to sequence homology, cell signalling activation, and agonist selectivity, the mGluRs have been divided into eight subtypes (from mGlu1 to mGlu8). These subtypes comprise three different subgroups (from I to III) [38]. Group I mGluRs (mGlu1 and mGlu5) are functionally linked to polyphosphoinositide (PI) hydrolysis *Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition… DOI: http://dx.doi.org/10.5772/intechopen.103760*

**Figure 3.**

*A reconstruction of possible AA ionotropic receptors in the CNS. The images were created using the data collected in the Protein Data Bank (PDB) (https://www.rcsb.org/). The scaled images show GlyR (6UBS, Danio rerio, [44]), AMPAR (5IDE, Rattus norvegicus, [45]), KAR (6KZM, Rattus norvegicus, [46]) and NMDAR (7EOQ, Homo sapiens, [47]).*

and are negatively coupled with K+ channels. Both group II (mGlu2 and mGlu3) and group III (mGlu4, mGlu6, mGlu7, and mGlu8) mGluRs negatively regulate adenylate cyclase and activate mitogen-activated protein kinase (MAPK) and PI-3-kinase pathways [39]. mGluRs are usually localized on synaptic and extrasynaptic membranes in both glia and neurons. Group I mGluRs are generally postsynaptic, surrounding ionotropic receptors, and modulate depolarization and synaptic excitability. Groups II and III are mostly expressed at the presynaptic level and control the release of neurotransmitters [39, 40]. mGluRs are heavily expressed throughout the basal ganglia (BG), where they modulate neuronal excitability, transmitter release, and long-term synaptic plasticity [41]. These receptors are coupled to different G proteins and modulate slow postsynaptic neuronal responses, either through presynaptic or postsynaptic machinery or through modulation of astrocyte function [42]. mGluRs are highly and diffusely expressed in glial cells. On the one hand, this increases the options for therapeutic interventions, but on the other hand, it makes it even more difficult to selectively target single receptors to yield neuroprotection (**Figure 3**) [43].

Glycine receptors (GlyRs), along with certain γ-aminobutyric acid receptors (GABAARs), are the principal determinants of fast inhibitory synaptic neurotransmission in the central nervous system (CNS). GlyR and GABAAR belong to the superfamily of pentameric ligand-gated ion channels (pLGICs) [33]. The two neurotransmitters (glycine and GABA) may be functionally interchangeable, and the multiple receptor subtypes with inhibitory influences provide diverse mechanisms for maintaining inhibitory homeostasis [35]. Inhibitory glycine receptors (GlyRs) are anion-selective ligand-gated ion channels (LGICs), which, together with GABAA receptors (GABAARs), nicotinic acetylcholine receptors (nAChRs), and serotonin type 3 receptors (5HT-3), form the eukaryotic Cys-loop family [36]. Several endogenous molecules, including neurotransmitters and neuromodulators (such as glutamate, Zn, and Ni), and exogenous substances, such as anaesthetics and alcohols, modulate GlyR function [40].
