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Journal of Molecular Modeling Apr 2019The complexes of selected long-chain arylpiperazines with homology models of 5-HT, 5-HT, and 5-HT receptors were investigated using quantum mechanical methods. The...
The complexes of selected long-chain arylpiperazines with homology models of 5-HT, 5-HT, and 5-HT receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand-receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT and 5-HT two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.
Topics: Binding Sites; Humans; Ligands; Models, Molecular; Piperazines; Protein Binding; Receptors, Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists
PubMed: 30955095
DOI: 10.1007/s00894-019-3995-6 -
Journal of Cell Science May 2012Serotonin receptors 5-HT(1A) and 5-HT(7) are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been...
Serotonin receptors 5-HT(1A) and 5-HT(7) are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT(1A) and 5-HT(7) receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either of 5-HT(1A) or 5-HT(7) receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT(7)-5-HT(7) homodimers, followed by the 5-HT(7)-5-HT(1A) heterodimers and 5-HT(1A)-5-HT(1A) homodimers. Functionally, heterodimerization decreases 5-HT(1A)-receptor-mediated activation of G(i) protein without affecting 5-HT(7)-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT(1A) receptor to activate G-protein-gated inwardly rectifying potassium channels in a heterologous system. The inhibitory effect on such channels was also preserved in hippocampal neurons, demonstrating a physiological relevance of heteromerization in vivo. In addition, heterodimerization is crucially involved in initiation of the serotonin-mediated 5-HT(1A) receptor internalization and also enhances the ability of the 5-HT(1A) receptor to activate the mitogen-activated protein kinases. Finally, we found that production of 5-HT(7) receptors in the hippocampus continuously decreases during postnatal development, indicating that the relative concentration of 5-HT(1A)-5-HT(7) heterodimers and, consequently, their functional importance undergoes pronounced developmental changes.
Topics: Animals; Brain; Cell Line, Tumor; Dimerization; Mice; Neurons; Protein Binding; Protein Transport; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Signal Transduction
PubMed: 22357950
DOI: 10.1242/jcs.101337 -
Advances in Biochemical... 1982
Review
Topics: Adenylyl Cyclases; Animals; Binding, Competitive; Ligands; Lysergic Acid Diethylamide; Rats; Receptors, Serotonin; Serotonin; Spiperone
PubMed: 6753508
DOI: No ID Found -
Medicinal Research Reviews Nov 1993
Review
Topics: Animals; Brain Chemistry; Digestive System; Humans; Receptors, Serotonin; Reference Values; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 8258998
DOI: 10.1002/med.2610130603 -
International Clinical... 1992Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline and... (Review)
Review
Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline and morphine to block contractions of intestinal smooth muscle caused by serotonin. The subsequent location of specific ligand binding sites for serotonin in the brain has led to the identification of at least eight serotonin receptor sub-types in rat brain. While there is some controversy over the functional importance of many of these receptor sub-types, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor sub-family which may be coupled either to adenylate cyclase (most 5-HT1 sub-types) or phosphatidyl inositol (5-HT2 sub-types). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand gated ion channel super-family. The cloning of three of the serotonin receptor sub-types in 1989 (5-HT1A, 5-HT1C and 5-HT2) has been of importance in enabling the receptor sub-types to be classified as specific protein molecules encoded by specific genes. The problem now arises with regard to the linking of the changes in the cellular activity of the various receptor sub-types with the plethora of behavioural changes that arise as a consequence of the actions of serotonin in the brain. The present review summarizes the evidence implicating the role of specific serotonin receptor sub-types in eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor sub-types and their possible involvement in the aetiology of these diseases is shown in Table 2.
Topics: Animals; Humans; Receptors, Serotonin
PubMed: 1624753
DOI: 10.1097/00004850-199200710-00002 -
Neuroreport Dec 1996Binding sites for [3H]lysergic acid diethylamide (LSD), a serotonin receptor agonist, were identified in planarian membranes by ligand binding studies. The Kd and Bmax...
Binding sites for [3H]lysergic acid diethylamide (LSD), a serotonin receptor agonist, were identified in planarian membranes by ligand binding studies. The Kd and Bmax values were approximately 4 microM and 0.2 pmol mg-1 protein, respectively. The serotonin (5-HT) receptor antagonists methiothepin and dihydroergocriptine were also efficient displacers of [3H]LSD binding. When planarians were decapitated in the presence of these antagonists, head regeneration was significantly retarded. These results suggest that planarians possess LSD binding sites which are involved in the process of regeneration. Furthermore, we found a putative (5-HT) receptor expressed in planarians by the degenerate primer polymerase chain reaction.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amino Acid Sequence; Animals; Base Sequence; DNA Primers; Ligands; Lysergic Acid Diethylamide; Molecular Sequence Data; Nerve Regeneration; Planarians; Polymerase Chain Reaction; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Thermodynamics
PubMed: 9051775
DOI: 10.1097/00001756-199612200-00035 -
Neuropsychopharmacology : Official... Aug 1999For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular... (Review)
Review
For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HT2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.
Topics: 3T3 Cells; Amino Acid Sequence; Animals; Base Sequence; Humans; Lysergic Acid Diethylamide; Mice; Phosphatidylinositols; RNA Editing; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Recombinant Proteins; Sequence Alignment; Serotonin; Serotonin Receptor Agonists; Signal Transduction; Transfection
PubMed: 10432492
DOI: 10.1016/S0893-133X(99)00005-6 -
Indian Journal of Experimental Biology Dec 2002Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which... (Review)
Review
Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones. This evidence has led to the suggestion that drugs acting on 5-HT2C receptors have potential as novel antipsychotic and antidepressant agents and may also be used in the treatment of other neuropsychiatric disorders such as Parkinson's disease and psychoactive substance abuse.
Topics: Animals; Psychotropic Drugs; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin
PubMed: 12974395
DOI: No ID Found -
Pharmacology, Biochemistry, and Behavior Apr 20115-HT(6) receptors are relatively recently-discovered receptors. After an uncertain beginning, where results were ambiguous, findings are now apparently more congruent.... (Review)
Review
5-HT(6) receptors are relatively recently-discovered receptors. After an uncertain beginning, where results were ambiguous, findings are now apparently more congruent. Nevertheless, discrepancies still exist. The aim of the present manuscript is to point out some of these discrepancies, in order to reflect on the current status of the field of the 5-HT(6) receptor neuropharmacology, and where the field should move next. Examples of 5-HT(6) receptor ligand-induced changes in behavior, neurochemistry and binding highlight areas where discrepancies remain and further experimental attention is needed. Possible methodological as well as conceptual issues underlying the inconsistencies are considered in an effort to increase awareness of the need for more thorough consideration of these aspects in future research.
Topics: Animals; Behavior, Animal; Brain; Humans; Ligands; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 21192969
DOI: 10.1016/j.pbb.2010.12.021 -
Journal of Psychiatric Research 2000The aim of this study was to investigate the influence of serotonin receptors 2A, 2C and 1A gene variants on lithium prophylactic efficacy in mood disorders. One hundred...
The aim of this study was to investigate the influence of serotonin receptors 2A, 2C and 1A gene variants on lithium prophylactic efficacy in mood disorders. One hundred and twenty-four subjects affected by bipolar (n=102) and major depressive (n=22) disorder were followed prospectively for an average of 52 months and were typed for 5-HT2A (T102C: n=111, HTP: n=104), 5-HT2C (n=110) and 5-HT1A (n=61) variants. Both 5-HT2A and 5-HT2C variants were not associated with lithium outcome. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not influence results. No 5-HT1A gene variant was identified. 5-HT2A and 2C variants are not, therefore, associated with lithium prophylactic efficacy in mood disorders.
Topics: Adult; Antimanic Agents; Bipolar Disorder; Depressive Disorder, Major; Female; Follow-Up Studies; Genetic Variation; Genotype; Humans; Lithium Carbonate; Male; Middle Aged; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Retrospective Studies; Treatment Outcome
PubMed: 10758249
DOI: 10.1016/s0022-3956(00)00004-2