Molecular biology of 5-HT receptors

Hannon, Jason P.; Hoyer, Daniel

doi:10.1016/j.bbr.2008.03.020

Cited by 697 publications

(574 citation statements)

References 179 publications

Supporting

Mentioning

532

Contrasting

Unclassified

Order By: Relevance

“…This indoleamine binds to more than 15 receptors that are pharmacologically classified into seven families, 5-HT 1 through 5-HT 7 (with their respective subtypes). With the exception of the 5-HT 3 receptor subfamily, all the others are G protein-coupled receptors (Hannon & Hoyer 2002, Adayev et al 2005, Hannon & Hoyer 2008, Pytliaki et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

Jiménez-Trejo¹,

Tapia-Rodríguez²,

Cerbón³

et al. 2012

Reproduction

View full text Add to dashboard Cite

Serotonin (5-hydroxytryptamine; C 10 H 12 N 2 O (5-HT)) is produced in the CNS and in some cells of peripheral tissues. In the mammalian male reproductive system, both 5-HT and tryptophan hydroxylase (TPH) have been described in Leydig cells of the testis and in principal cells of the caput epididymis. In capacitated hamster sperm, it has been shown that 5-HT promotes the acrosomal reaction. The aim of this work was to explore the existence of components of the serotoninergic system and their relevance in human sperm physiology. We used both immunocytochemistry and western blot to detect serotoninergic markers such as 5-HT, TPH1, MAO A , 5-HT 1B , 5-HT 3 , and 5HT T ; HPLC for TPH enzymatic activity; Computer Assisted Semen Analysis assays to measure sperm motility parameters and pharmacological approaches to show the effect of 5-HT in sperm motility and tyrosine phosphorylation was assessed by western blot. We found the presence of serotoninergic markers (5-HT, TPH1, MAO A , 5-HT 1B , 5-HT 2A , 5-HT 3 , 5-HT T , and TPH enzymatic activity) in human sperm. In addition, we observed a significant increase in tyrosine phosphorylation and changes in sperm motility after 5-HT treatment. In conclusion, our data demonstrate the existence of components of a serotoninergic system in human sperm and support the notion for a functional role of 5-HT in mammalian sperm physiology, which can be modulated pharmacologically.

show abstract

Section: Introductionmentioning

confidence: 99%

Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

Jiménez-Trejo¹,

Tapia-Rodríguez²,

Cerbón³

et al. 2012

Reproduction

View full text Add to dashboard Cite

show abstract

“…The mixture was kept at reflux temperature for 2 h. After this time the reaction was quenched with water (50 mL) and extracted with AcOEt (3×30 mL). The organic layer was dried over anhydrous Na-2 SO 4 and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (AcOEt) to furnish 889 mg (74%) of a brown oil.…”

Section: Methodsmentioning

confidence: 99%

“…[1][2][3] The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field. [4][5][6][7] It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.…”

mentioning

confidence: 99%

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-hKey words indolylalkylarylpiperazine; 5-hydroxytryptamine 1A receptor; docking; binding; synthesis Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that mediates various physiological and pathological processes in the peripheral and central nervous system (CNS) by interacting with several different receptors.1-3) The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field.4-7) It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.8-10) The 5-HT 1A receptor is also implicated in many other physiopathological CNS processes and conditions such as neuroprotection, schizophrenia, Parkinson's and Alzheimer's diseases, acting alone or associated with other neurotransmitter receptors, especially dopamine receptors.Long-chain arylpiperazine derivatives are one of the most important classes of 5-HT 1A ligands. In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors.11-13) As a consequence, many compounds containing this scaffold bind with high affinity at 5-HT 1A receptors, but only a few of them also show high selectivity for 5-HT 1A over other receptors. 14)Structure-activity relationship (SAR) studies, performed with numerous generations of arylpiperazine derivatives, showed that CNS activity and both, receptor affinity and selectivity depend basically on the N-1-aryl substituent and a terminal fragment bound to the N-4 atom of the piperazine moiety by an alkyl chain. In these studies, this alkyl spacer is frequently composed of two to four methylene units. 15,16) On the other hand, the indole substructure is the basic element in a large number of biologically active natural and synthetic products. In fact, until this day, the indole motif is present in more than 400 drugs and 3000 patents.17) The range of applications for these therapeutically relevant compounds includes anti-inflammatory drugs, protein kinase C inhibitors, 5-HT agonists and antagonists, melatonin agonists and glucocorticoid receptor modulators.18) Studies on structural modifications of indolylalkylarylpiperazines carried out by Heinrich et al. 14,19) reported a high-affinity pattern for 5-HT 1A agonism and succeeded in optimizing selectivity over dopamine D 2 receptors. This structural pattern considers a C5-substituted indole ring bearing different functional groups and a parasubstituted arylpiperazine. In these studies, a four-carbon atom chain was employed as a linker of both heterocyclic moieties. On the other hand, a few studies on indolylalkylarylpiperazines containing a propyl chain as a linker have been reported regarding their 5-HT 1B/1D receptor affinity. 20,21) However, the influence of a propylic connecting chain on the affinity of this type ...

show abstract

“…(GPCRs) superfamily [1] and plays an important role in mediating mood effects in the brain where it is found at high concentrations in the hippocampus, lateral septum, cortical areas and the mesencephalic raphe nuclei [2]. Functionally, 5-HT 1A underlies the molecular mechanism of major depressive and anxiolytic disorders [3].…”

Section: -Hydroxytryptamine Receptor 1a (5-ht 1a ) Belongs To Class mentioning

confidence: 99%

“…Before protein insertion, the box contained 256 lipids (corresponding to an area per lipid of 0.64 nm 2 ) and circa 17000 water molecules. The protein was placed in the center of the box, and the overlapping molecules were removed.…”

mentioning

confidence: 99%

Zinc Is Involved in Depression by Modulating G Protein-Coupled Receptor Heterodimerization

et al. 2015

View full text Add to dashboard Cite

5-Hydroxytryptamine 1A receptor and galanin receptor 1 belong to the G-protein-coupled receptors superfamily and they have been described to heterodimerize triggering an anomalous physiological state that would underly depression. Zinc supplementation has been widely reported to improve treatment against major depressive disorder. Our work has focused on the study and characterization of these receptors and its relationships with zinc both under purified conditions and in cell culture. To this aim, we have designed a strategy to purify the receptors in a conformationally active state. We have used receptors tagged with the monoclonal Rho-1D4 antibody, and employed ligand assisted purification in order to successfully purify both receptors in a properly folded and active state. The interaction between both purified receptors has been analyzed by surface plasmon resonance in order to determine the kinetics of dimerization. Zinc effect on heteromer has also been tested using the same methodology, but exposing the 5-hydroxytryptamine 1A receptor to zinc before the binding experiment. These results, combined with FRET measurements, in the absence and presence of zinc, suggest that this ion is capable of disrupting this interaction. Moreover, molecular modelling suggests that there is a coincidence between zinc binding sites and heterodimerization interfaces for the serotonin receptor.Our results establish a rational explanation for the role of zinc in the molecular processes associated with receptor-receptor interactions and its relationship with depression, in agreement with previously reported evidence for the positive effects of zinc in depression treatment, and the involvement of our target dimer in the same disease.

show abstract

Molecular biology of 5-HT receptors

Cited by 697 publications

References 179 publications

Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

Evidence of 5-HT components in human sperm: implications for protein tyrosine phosphorylation and the physiology of motility

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Zinc Is Involved in Depression by Modulating G Protein-Coupled Receptor Heterodimerization

Contact Info

Product

Resources

About