Table 1 Genetic components of the serotonergic system
From: Genetic and biochemical changes of the serotonergic system in migraine pathobiology
Enzyme | Gene | Locus | Function | Significance for migraine |
Tryptophan hydroxylase 1 | TPH1 | 11p15.3-p14 | TPH1, peripheral form, converts tryptophan to 5 hydroxy tryptophan, rate-limiting step in the synthesis of 5-HT, determines the availability of 5-HT and its rate of production. | TPH enzymes regulate brain-specific serotonin deficiency, weak association [43]. |
Tryptophan hydroxylase 2 | TPH2 | 12q21.1 | TPH2, neuronal form, synthesis of serotonin. | Â |
Monoamine oxidase A | MAO-A | Xp11.3 | MAO-A, outer mitochondrial membrane, oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. | Enzymes metabolise triptans. |
Monoamine oxidase B | MAO-B | Xp11.23 | MAO-B, both subtypes have a widespread occurrence in the brain and in peripheral tissues. | MAO inhibitors promote the accumulation of monoamines and reduce uncontrolled vasodilation, and were used in treating migraine but discontinued due to side effects [73]. |
Amino acid decarboxylase | DDC | 7p12.2 | DDC, catalyses the decarboxylation of L-5-hydroxytryptophan to 5-HT and L-tryptophan to tryptamine. | Gene variations have been investigated in relation to neuropsychiatric disorders. |
Aldehyde dehydrogenase 2 | ALDH2 | 12q24.2 | ALDH2, located in mitochondria produce 5-hydroxyindole acetic acid as the major excreted metabolite of serotonin. | Â |
Receptor Protein | Gene | Locus | Potential and mechanism | Significance for migraine |
5HT1 | HTR1A | 5q11.2-q13 | Inhibitory, decreasing cellular levels of cAMP | Â |
HTR1B | 6q13 | Â | Co-localization of 5HT1B, 5HT1D and HTR1F receptor subtypes in vestibular ganglia [20, 74]. Triptans have high affinity for serotonin receptors. | |
HTR1D | 1p36.3-p34.3 | Â | Â | |
HTR1E | 6q14-q15 | Â | Â | |
HTR1F | 3p12 | Â | Lasmiditan is a 5-HT1F receptor agonist by non-vascular mechanism [75]. | |
5HT2 | HTR2A | 13q14-q21 | Excitatory, increasing cellular levels of IP3 and DAG | Cortical density of the excitatory 5-HT2 receptor, which is involved in pain processing, is not altered interictally in migraine patients [76]. |
HTR2B | 2q36.3-q37.1 | Â | Â | |
HTR2C | Xq24 | Â | Positive association in SNP in HTR2C promoter in Turkish population with migraine [40]. | |
5HT3 | HTR3A | 11q23.1 | Excitatory, depolarizing plasma membrane | Role in facilitation of inflammatory and neuropathic pain [77]. |
HTR3B | 11q23.1 | Â | Â | |
HTR3C | 3q27.1 | Â | Â | |
HTR3D | 3q27.1 | Â | Â | |
HTR3E | 3q27.1 | Â | Â | |
5HT4 | HTR4A | 5q31-q33 | Excitatory, increasing cellular levels of cAMP | Central 5-HT4 receptor binding might serve as a biomarker of serotonergic tonus in the human brain [78]. |
5HT5 | HTR5A | 7q36.1 | Inhibitory, Decreasing cellular levels of cAMP | Â |
HTR5B | 2q14.1 | Â | Â | |
5HT6 | HTR6A | 1p36-p35 | Excitatory, increasing cellular levels of cAMP | Â |
5HT7 | HTR7A | 10q21-q24 | Excitatory, increasing cellular levels of cAMP | 5-HT7 receptor activation promotes NMDA-evoked currents [79, 80]. 5-HT7 receptor has differing roles in peripheral versus central pain mediation and is clinically relevant for the treatment of depression, a migraine co-morbidity [81]. |
Transporter protein | Gene | Locus | Function | Significance for migraine |
Serotonin transporter, SERT | SLC6A4 | 17q11.2 | Reuptakes serotonin from the synapse, role in psychiatric disease | Meta-analyses by the groups of Liu and Schurks report a positive association with SERT and migraine [27, 28]. |
Plasma membrane monoamine transporter, PMAT | SLC629A4 | 7p22.1 | Transport of both serotonin and dopamine | Â |