Physiol. Res. 60: 15-25, 2011 https://doi.org/10.33549/physiolres.931903 REVIEW Serotonin Receptors – From Molecular Biology to Clinical Applications M. PYTLIAK1, V. VARGOVÁ2, V. MECHÍROVÁ1, M. FELŠÖCI1 1First Internal Clinic, Louis Pasteur University Hospital and Faculty of Medicine, Šafárik University, Košice, Slovak Republic, 2Third Internal Clinic, Louis Pasteur University Hospital and Faculty of Medicine, Šafárik University, Košice, Slovak Republic Received October 5, 2009 Accepted May 26, 2010 On-line October 15, 2010 Summary neurotransmitters at synapses of nerve cells. It has a similar Serotonin (5-hydroxytryptamine) is an ubiquitary monoamine chemical structure with tryptamine, dimethyltryptamine, acting as one of the neurotransmitters at synapses of nerve cells. diethytryptamine, melatonin and bufothein belonging to Serotonin acts through several receptor types and subtypes. The the group of indolalkylamins (Doggrell 2003). profusion of 5-HT receptors should eventually allow a better In addition to the nerve endings, serotonin was understanding of the different and complex processes in which found in the bodies of neurons, enterochromafinne serotonin is involved. Its role is expected in the etiology of stomach cells and platelets. Biosynthesis of serotonin several diseases, including depression, schizophrenia, anxiety and begins with hydroxylation of an essential amino acid panic disorders, migraine, hypertension, pulmonary hypertension, L-tryptophan. L-tryptophan is transported through the eating disorders, vomiting and irritable bowel syndromes. In the blood-brain barrier into the brain using the neutral amino past 20 years, seven distinct families of 5-HT receptors have acids transmitter, on which competes with other amino been identified and various subpopulations have been described acids – phenylalanine, leucine and methionine. for several of them. Increasing number of 5-HT receptors has Tryptophanhydroxylase is the first step and speed made it difficult to unravel the role of 5-HT receptor limiting factor of 5-HT synthesis. This enzyme was found subpopulations due to the lack of suitable selective agents. The in the brain only in the serotoninergic neurons. It enables present review describes the different populations and conversion of tryptophan into 5-hydroxytryptophan, nomenclature of recently discovered 5-HT receptors and their followed by the decarbolization mediated by aromatic pharmacological relevance. L-amino acid decarboxylase onto 5-hydroxytryptamine Key words (serotonin) – Figure 1 (Berger 2009). Serotonin • Serotonin receptors • Antidepressants • Behavior Serotonin was discovered in the late 1940s and within a next decade, there were indications for its Corresponding author existence in the central nervous system of animals and its Marek Pytliak, 1st Internal Clinic , Medical Faculty, P. J. Safarik neurotransmitter function. By the late 1950s, evidence for University, Trieda SNP 1, 040 11 Kosice, Slovak Republic. E-mail: 5-HT receptor heterogeneity was found in the periphery [email protected] and in 1979, two distinct populations of 5-HT binding sites were identified in rat brain: 5-HT1 and 5-HT2 sites Introduction (Peroutka 1984). In the recent 20 years, seven distinct families of 5-HT receptors have been identified (Table 1) Serotonin – 5-hydroxytryptamine (5-HT) is an and various subpopulations have been described for ubiquitary monoamine acting as one of the several of these (e.g. Nichols and Nichols 2008). PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) © 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 16 Pytliak et al. Vol. 60 Fig. 1. Synthesis of serotonin from tryptophan (the hydroxylation of tryptophan trough tryptophanhydroxylase is a speed limiting step in the serotonin production). Source: own figure Table 1. Families of 5-HT receptors. Family Potential Type Mechanism of action 5-HT1 Inhibitory Gi/G0-protein coupled Decreasing intracellular concentration of cAMP Increasing intracellular concentration of IP3 and 5-HT Excitatory G -protein coupled 2 q11 DAG + + 5-HT3 Excitatory Ligand-gated Na /K channel Depolarization of cell plasma membrane 5-HT4 Excitatory Gs-protein coupled Increasing intracellular concentration of cAMP 5-HT5 Inhibitory Gi/G0-protein coupled Decreasing intracellular concentration of cAMP 5-HT6 Excitatory Gs-protein coupled Increasing intracellular concentration of cAMP 5-HT7 Excitatory Gs-protein coupled Increasing intracellular concentration of cAMP IP3: inositol trisphosphate; DAG: diacylglycerol; cAMP: cyclic adenosine monophosphate. Sources: Hannon and Hoyer 2002, Berger et al. 2009 At least 20 subpopulations of 5-HT receptors the inhibition of "discharge" of neurons, regulation of the have been cloned, yet (Table 2). production of ACTH (but not prolactin), and regulation of behavior and eating (Wang et al. 2009). They play 5-HT1 receptors probably an important role in the emergence of anxiety. This group consists of five receptor subtypes This observation was confirmed by studies with knockout (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F), which are gene for this subtype of 5-HT1 receptor in mice. The structurally identical in humans to 40-63 %. There is no animals showed increased fear in many experimental 5-HT1C receptor, as it was reclassified as the 5-HT2C conditions (Klemenhagen et al. 2006). Moreover, 5-HT1A receptor. They are mostly (but not exclusively) associated antagonists (buspiron, gepiron) are used or developed for with Gi/G0 proteins and inhibit production of cAMP. the treatment of anxiety and depression. Antagonists of Fully functional 5-HT1A, 5-HT1B and 5-HT1D receptors 5-HT1A receptor and β-blocker pindolol improve the have been found in many tissues of various species effectiveness of selective serotonin reuptake inhibitors – (Hoyer and Martin 1997). SSRIs in treatment of depression (Artigas et al. 2006). The 5-HT1A receptor is the most extensively The antianxiety actions of 5-HT1A (partial) agonists may distributed of all the 5-HT receptors. In the central provide primarily presynaptic somatodendritic 5-HT1A nervous system, 5-HT1A receptors are present in high receptors (leading to reduced release of 5-HT in terminal density in the cerebral cortex, hippocampus, septum, areas), whereas the antidepressant action of 5-HT1A amygdala, and raphe nucelus, but they were proven in agents may primarily provide postsynaptic 5-HT1A small amounts in the basal ganglia and thalamus as well receptors (De Vry 1995). Certain 5-HT1A agents display (el Mestikawy et al. 1993). However, they can be found antiaggressive behavior, and measurement of the density also in myentericus plexus and whole gastrointestinal of 5-HT1A receptors in frontal cortex of suicide victims tract. In the brain, 5-HT1A receptors act as autoreceptors reveals that nonviolent suicide victims had a significantly as well as postsynaptic receptors. They are involved in higher Bmax, compared with controls and violent 2011 Serotonin Receptors 17 Table 2. Subpopulations of 5-HT receptors families. Receptor Effects and functions Agonists Antagonists 5-HT1A CNS: Aggression, Anxiety, Addiction, Appetite, buspiron, spiperone, alprenolol, Emesis, Impulsivity, Memory, Mood, Nausea, dihydroergotamine, asenapine, cyanopindolol, Nociception, Respiration, Sleep, Sociability, eltoprazine, ergotamine, iodocyanopindolol, Thermoregulation, Sexual behavior flesinoxan, flibanserin, lecozotan, methiothepin, Cardiovascular system: Blood pressure, Heart gepirone, ipsapirone, oxprenolol, pindolol, rate, Cardiovascular function, Vasoconstriction, methysergide, quetiapine, propanolol Penile erection tandospirone, urapidil, Other: Pupil dilation yohimbine, ziprasidone 5-HT1B CNS: Aggression, Anxiety, Learning, Addiction, dihydroergotamine, yohimbine, alprenolol, Locomotion, Memory, Mood, Sexual behavior eletriptan, eltoprazine, asenapine, cyanopindolol , Vessels: Pulmonary vasoconstriction, Penile ergotamine, methysergide, iodocyanopindolol, erection sumatriptan, zolmitriptan isamoltane, metergoline, methiothepin, oxprenolol, pindolol, propanolol 5-HT1D CNS: Locomotion, Anxiety sumatriptan, almotriptan, ketanserin, metergoline, Vessels: Cerebral vasoconstriction dihydroergotamine, methiothepin, rRauwolscine, eletriptan, ergotamine, ritanserin frovatriptan, methysergide, naratriptan, rizatriptan, yohimbine, zolmitriptan 5-HT1E CNS: Memory eletriptan, methysergide, methiothepin tryptamine 5-HT1F Blood Vessels: Vasoconstriction eletriptan, naratriptan, methiothepin CNS: Locomotion? Anxiety? sumatriptan 5-HT2A CNS: Anxiety, Appetite, Addiction, Cognition, bufotenin, ergonovine, aripiprazole, clozapine, Imagination, Learning, Memory, Mood, lisuride, LSD (in CNS), cyproheptadine, eplivanserin, Perception, Sexual behaviour, Sleep, mescaline, myristicin, etoperidone, iloperidone, Thermoregulation psilocin, psilocybin, ketanserin, methysergide, Smooth muscles: Contraction yohimbine mirtazapine, nefazodone, Vessels: Vasoconstriction, Vasodilation olanzapine, quetiapine, Platelets: Aggregation risperidone, ritanserin, trazodone, ziprasidone 5-HT2B CNS: Anxiety, Appetite, Sleep α-metyl-5-HT, agomelatine, asenapine, Gastrointestinal tract: GI motility fenfluramine, LSD ketanserin, LSD (PNS), Vessels: Vasoconstriction (in CNS), norfenfluramine methysergide, ritanserin, Cardiovascular system: Cardiovascular function tegaserod, yohimbine 5-HT2C CNS: Anxiety, Appetite,