Illustration showing neurotransmitters synthesis, storage in vesicles, transport to presynaptic membrane upon membrane depolarization and Ca²⁺ release, then release of vesicle content into the synapse and re-uptake by specific transporters (SERT, DAT). Positive action of PKC phosphorylation increasing the recycling vesicle pool is also depicted. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine synthesis, catalyzing the conversion of tyrosine into 3,4-dihydroxy-phenylalanine (L-dopa). Catecholamines are synthesized in the nerves at the site of their release. TH requires BH4 and Fe⁺² as cofactors, and it is heavily modulated at both transcriptional and post-translational levels. It is inhibited by end products at two different levels. The first is a feedback mechanism on the enzyme activity that depends on the local concentration of catecholamines, and the second is the sequestration of the enzyme by long-term binding of the catalytic site to Fe⁺³ ions. The enzyme is heavily phosphorylated at four major N-terminal serine sites, which are the substrates for several protein kinases, including PKC. Phosphorylation of these serine residues results in enzyme activation, increase in enzyme activity or both [26]. Tryptophan hydroxylase (TPH) is the first enzyme in serotonin synthesis, converting tryptophan to 5-hydroxytryptophan. The level of tryptophan in the brain depends not only on blood levels but also on the levels of the other neutral amino acids, as they all share a common transporter through the blood–brain barrier [26]. Aromatic amino acid decarboxylase (AADC) catalyzes the conversion of L-dopa to dopamine. This enzyme also catalyzes the decarboxylation of 5-hydroxytryptophan to 5-hydroxytryptamine (serotonin). It is a pyridoxine-dependent enzyme. AADC is also heavily regulated at pre- and post-translational levels by receptors and protein kinases [26]. Biogenic amines are stored after synthesis in vesicles and are released by an exocytotic mechanism. Neurotransmitters are transported into vesicles by secondary transporters that use the H⁺ gradient established by a V-type H⁺-ATPase. There are three transport families in humans, named SLC17 (VGLUT, VNUT), SLC18 (VMAT), and SLC32 (VIAAT) [27]. Exocytosis is triggered by intracellular Ca⁺² and regulated by synaptotagmin via interaction with the SNARE/complexin complex. Other important proteins in vesicular exocytosis are synaptobrevin, syntaxin, synaptophysin, synaptogyrin, otoferlin, and SNAP25. These participate in the vesicle priming, docking, and opening of the synaptic vesicles and releasing their contents into the synaptic cleft [28]. Actin is a regulator of synaptic vesicle mobilization and exocytosis, and there are several regulators of cytoskeleton dynamics that act on proteins in the ADF/cofilin family. Actin is the most prominent cytoskeletal protein at synapses, being abundantly present in presynaptic terminals and postsynaptic dendritic spines [29]. Neurotransmitters activate cell-surface receptors that operate via distinct signaling mechanisms. These receptors include ligand-gated ion channels, receptors with intrinsic guanylyl cyclase activity, receptors with intrinsic or associated tyrosine kinase activity, or G-protein coupled receptors. The principal process for termination of monoaminergic neurotransmission is the uptake of dopamine and serotonin into the nerve terminals through the monoamine transporters DAT (dopamine transporter) and SERT (serotonin transporter). Monoamine transporters have functional regulation at different levels: long-term regulation at the gene level, short-term regulation through protein phosphorylation, and trafficking-dependent and trafficking-independent regulation (altered transporter surface expression). Abbreviations: P – phosphorylation, + activation, SERT – serotonin transporter, DAT – dopamine transporter, CaM – calmodulin, VMAT2 – vesicular monoamine transporter 2, PAH – phenylalanine hydroxylase, TH – tyrosine hydroxylase, AADC – aromatic L-amino acid decarboxylase, TPH – tryptophan hydroxylase, PKC – protein kinase C (original illustration by Vicky Earle)