5-HT 2B receptor

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5-HT 2B receptor
5-HT2B receptor
Structural model of the 5-HT 2B receptor in complex with ergotamine according to PDB  4IB4
Properties of human protein
Mass / length primary structure 481 AS ; 54.3  kDa
Secondary to quaternary structure 7TM (monomer)
Identifier
Gene names HTR2B  ; 5-HT (2B), 5-HT2B
External IDs
Occurrence
Homology family Rhodopsin-like receptors
Parent taxon Eukaryotes

The 5-HT 2B receptor ( 5-HT 2B for short ) is a protein from the serotonin receptor family (5-HT receptors) that can be activated by serotonin , an endogenous tissue hormone and neurotransmitter . In the human body, the 5-HT 2B receptor occurs in particular in the cell membrane of cells of the smooth muscles and the vascular endothelium and in small quantities in nerve cells . Together with its agonist serotonin, this receptor plays an important role in the development and function of the cardiovascular system . At the molecular level, this G protein-coupled receptor mediates its effects via the activation of heterotrimeric G proteins .

biochemistry

genetics

The human 5-HT 2B receptor was first cloned in 1994 . He is a HTR2B - gene on chromosome 2 , locus 2q36.3-q37.1 encodes . The DNA coding region contains two introns . A single nucleotide polymorphism that leads to a dysfunctional 5-HT 2B receptor has been associated with increased impulsiveness . A mutation that leads to a fully functional receptor that is permanently expressed on the cell membrane was also found to be a possible cause of the development of pulmonary hypertension after taking appetite suppressants .

Protein structure

The human 5-HT 2B receptor protein consists of 481 amino acids . With the help of the X-ray crystal structure analysis, a predicted structure with seven helical transmembrane domains ( heptahelical receptor ) could be confirmed.

Helix VI is mainly involved in signal transmission by G proteins, while conformational changes in Helix VII are associated with transmission by β-arrestins. In the 5-HT 2B -receptor-ergotamine complex, helix VII is in the activated conformational state, whereas helix VI is only partially activated. This reflects the strong β-arrestin bias of ergotamine at this receptor, as can be observed in pharmacological assays (see also section 5-HT 2B agonists ).

Signal transduction

At the molecular level, stimulation of 5-HT 2B receptors leads to activation of G q / 11 proteins and activation of phospholipase C in conjunction with the release of Ca 2+ from intracellular stores. As a result, various intracellular signal transduction pathways are activated, which lead to contraction of smooth muscle cells. Furthermore, stimulation of 5-HT 2B receptors activates G 12/13 proteins, the NO synthases eNOS and iNOS, phospholipase A₂ , NAD (P) H oxidase and the sodium proton exchanger 1 as well as cell cycle activation and activation of the ERK signaling pathway .

function

Cardiovascular system

By stimulating 5-HT 2B receptors, serotonin leads to a contraction of the smooth muscles of the cardiovascular system. In some blood vessels , serotonin can also lead to relaxation by activating this receptor and releasing nitric oxide from the endothelium .

Animal studies with knockout mice have also shown that the serotonin receptor is important for the development of the cardiovascular system, especially that of the heart . In contrast, stimulation of the 5-HT 2B receptor leads to fibrosis of the heart. This receptor also plays a pathological role in the development of primary pulmonary hypertension.

Gastrointestinal tract

5-HT 2B receptors are also found in high density in the neurons and smooth muscles of the gastrointestinal tract . Here they play an important role in the development of the intestinal nervous system and gastrointestinal motility .

Central nervous system

Although 5-HT 2B receptors could only be detected in very small amounts in the central nervous system, it is assumed that this receptor is involved in the antidepressant effect of selective serotonin reuptake inhibitors and in the psychological effect of designer drugs.

The 5-HT 2B receptor is one of those serotonin receptor types via which pain stimuli are transmitted. See also the section Serotonin # Pain .

pharmacology

5-HT 2B / 2C agonist dexfenfluramine
Ergotamine: high β-arrestin bias

The 5-HT 2B receptor not only has a very close genetic and structural relationship to the 5-HT 2C receptor. The two receptors are also very similar pharmacologically . The 5-HT 2B receptor is not currently a target for drug development, although there may be therapeutic potential for antagonists in the treatment of chronic liver disease. Due to the connection between activation of this receptor and the occurrence of cardiac valve damage , the 5-HT 2B receptor is classified as an antitarget for agonists . Tests for a possible agonism at the 5-HT 2B receptor are usually carried out in the early phases of drug development . The administration of 5-HT 2B receptor antagonists in the presence of serotonin syndrome is contraindicated; they can further exacerbate symptoms of the syndrome.

Agonists

Selective 5-HT 2B receptor agonists , such as BW-723C86 , are only of experimental significance.

Prodrugs of the nonselective 5-HT 2B / 2C receptor agonists norfenfluramine and dexnorfenfluramine, such as fenfluramine , dexfenfluramine and benfluorex , have been used as appetite suppressants since the 1970s . Due to the increased observation of cases of heart valve damage and pulmonary hypertension, these nonselective 5-HT 2B / 2C receptor agonists were withdrawn from the market in the 1990s and 2000s. After the knowledge that stimulation of the 5-HT 2C receptor is responsible for the appetite suppressing effect and the agonism at the 5-HT 2B receptor is responsible for the side effects , selective 5-HT 2C receptor agonists were developed as new appetite suppressants. Lorcaserin , which was approved in the USA in 2012, shows over 100-fold selectivity for 5-HT 2C versus 5-HT 2B receptors.

Numerous other, especially older, drugs with a nonselective action profile can stimulate the 5-HT 2B receptor as agonists. In addition to dihydroergotamine , ergometrine , methysergide , methylergometrine , pergolide and cabergoline , for which an increased incidence of heart valve damage is known, also guanfacine , quinidine , xylometazoline , oxymetazoline , fenoldopam .

Some ergoline derivatives, in particular ergotamine and dihydroergotamine, show a high functional selectivity in that they prefer signal transmission via β- arrestin ; their bias factors are 230 and 185, respectively; in the same sense, cabergoline and LSD each have a factor of 100. Ropinirole , a low-affinity 5-HT 2B receptor agonist, on the other hand, prefers the calcium ion flux with less bias .

Antagonists

RS-127,445

5-HT 2B receptor antagonists exist in numerous structure-typical variants. Selective antagonists, such as RS-127,445 and the tryptoline LY-272,015, are used experimentally in particular in research and development. RS-127,455 has high affinity and binds 1000 times more strongly to the 5-HT 2B receptor than to the 5-HT 2A and 5-HT 2C isoforms . Antagonists have meanwhile been developed that achieve selectivity factors of well over 10,000 in this regard.

Many therapeutically used drugs are non-selective 5-HT 2B receptor antagonists. The migraine prophylactic effectiveness of lisuride and pizotifen is attributed to their potent 5-HT 2B receptor-antagonistic effect. The platelet aggregation inhibitor sarpogrelat and the prokinetic tegaserod also have distinctive 5-HT 2B receptor-antagonistic properties. This also applies to the neuroleptics asenapine , aripiprazole and clozapine . The antidepressant Mianserin and the Rauwolfia alkaloid yohimbine can also be assigned to this category.

Web links

Individual evidence

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