5-HT 1B receptor
| 5-HT 1B receptor | ||
|---|---|---|
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| Structural model of the 5-HT 1B receptor in complex with ergotamine | ||
| Properties of human protein | ||
| Mass / length primary structure | 390 AS ; 43.6 kDa | |
| Secondary to quaternary structure | 7TM | |
| Identifier | ||
| Gene name | HTR1B | |
| External IDs | ||
| Occurrence | ||
| Parent taxon | Vertebrates | |
The 5-HT 1B receptor ( 5-HT 1B for short , previously also 5-HT 1D β- receptor , from 5-hydroxytryptamine ( serotonin )) is a protein from the family of serotonin receptors (5-HT receptors), which can be activated by serotonin, an endogenous tissue hormone and neurotransmitter . In the human body, the 5-HT 1B receptor occurs in particular in the cell membrane of cells of the smooth muscles and the central nervous system . Together with its agonist serotonin, this receptor plays an important role in transmitting signals in the nervous system ( neurotransmission ). At the molecular level, this G protein-coupled receptor mediates its effects via the activation of heterotrimeric G proteins . Drugs that stimulate 5-HT 1B receptors are used in the acute treatment of migraines .
biochemistry
genetics
The human 5-HT 1B receptor was first cloned in 1992 . It is encoded by a gene on chromosome 6 on the gene locus 6q13, the HTR1B gene. The coding DNA region is intron-free . With a sequence match of 63% (77% in the transmembrane regions), the human 5-HT 1B receptor is very closely related to the 5-HT 1D receptor .
Protein structure
The human 5-HT 1B receptor protein consists of 390 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.
Ligand recognition: The orthosteric binding cavity lies in the deeper inner area of the receptor and is determined by the helices III, V, VI, VII and ECL2. It is less polar than those in the receptors of other monoamines , such as noradrenaline , dopamine or histamine . Ligands with a basic or partial tryptamine structure form a salt bridge with the carboxy group of an aspartic acid member of the receptor via their amine function . This ionogenic binding site is also found in other monoamine receptors. The nitrogen- bonded hydrogen atom of the indole forms a hydrogen bond via the hydroxy group of a threonine . This binding pattern is widespread in the serotonin receptor family. The indole is laterally framed by serine - and alanine residues of the helix V. To the binding pocket in the receptor core joins another bag, which in the extracellular is the entrance area of the receptor and can accommodate Ligandanteile as in ergotamine as a larger tripeptide rest of Lysergamids are found. However, the tripeptide residue seems to contribute little to the affinity. An allosteric binding site is suspected in this pocket .
There are species-specific differences in the receptor which are expressed in the fact that the affinity of some adrenergic ligands at the 5-HT 1B receptor is significantly higher in rodents than in humans.
Signal transduction
At the molecular level, stimulation of 5-HT 1B receptors leads to activation of G i / o proteins and an inhibition of adenylyl cyclases as well as opening of potassium channels . Furthermore, stimulation of 5-HT 1B receptors activates phospholipases C and D , NO synthases and the ERK signaling pathway .
function
Central nervous system
In the central nervous system, 5-HT 1B receptors occur particularly on nerve endings. A particularly high density of these receptors can be found in the basal ganglia , the striatum and the frontal cortex . Neural 5-HT 1B receptors can act as presynaptic receptors to control the release of serotonin ( autoreceptors ). In addition, as heteroreceptors , they inhibit the release of other neurotransmitters , such as the release of acetylcholine , dopamine , glutamate , noradrenaline and GABA . In addition, the activation of 5-HT 1B receptors inhibits the release of inflammation-mediating peptides, such as calcitonin gene-related peptides . 5-HT 1B receptors in the central nervous system play a role in aggression, fear, mood, addiction, sexual behavior, locomotion and learning.
Cardiovascular system
By stimulating 5-HT 1B receptors, serotonin leads to a contraction of the smooth muscles of the cardiovascular system. In addition to the 5-HT 2A receptors, they are the most important blood vessel- contracting serotonin receptors. In the pulmonary circulation in particular, this receptor is involved in the regulation of blood vessel tone. The 5-HT 1B receptor-mediated contraction of intracranial arteries of the coronary arteries is also of particular importance .
pharmacology
The 5-HT 1B receptor not only has a very close genetic and structural relationship to the 5-HT 1D receptor. The two receptors are also difficult to distinguish from one another pharmacologically .
Agonists
5-HT 1B receptor agonists are used in the acute treatment of migraine attacks because of their intracranial artery contracting and inflammation mediator release inhibiting effect. The therapeutically used non-selective 5-HT 1B receptor agonists include the ergot alkaloids , such as ergotamine .
The experimentally used 5-carboxamidotryptamine , a 5-HT 1/7 receptor agonist , has a comparatively higher selectivity . On the basis of its structure, selective 5-HT 1B / 1D receptor agonists, the triptans used today as the first choice in acute therapy for migraine , were developed. In 1991, sumatriptan, the first representative of this substance class, was approved. This was followed by naratriptan , rizatriptan , eletriptan , zolmitriptan , almotriptan and frovatriptan , which differ from the prototype sumatriptan mainly in their pharmacokinetics .
Compared to several other ligands at this receptor, cabergoline shows a notable preference for signal transmission by β-arrestin, with a bias factor of 70.
Antagonists
In contrast to the 5-HT 1B receptor agonism, the 5-HT 1B receptor antagonism has not yet found any therapeutic use. Next Mutterkornalkaloidderivaten Regardless, also have some other drugs such as the antipsychotic methiothepine and is used to treat erectile dysfunction used yohimbine , relevant 5-HT 1B -rezeptorantagonistische properties.
Selective 5-HT 1B receptor antagonists, such as, for example, SB-216,641 , are used experimentally in particular in research and development.
Web links
Individual evidence
- ↑ Weinshank RL, Zgombick JM, Macchi MJ, Branchek TA, Hartig PR: Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta . In: Proc. Natl. Acad. Sci. USA . 89, No. 8, April 1992, pp. 3630-4. PMID 1565658 . PMC 48922 (free full text).
- ↑ a b c Wang C, Jiang Y, Ma J, et al. : Structural Basis for Molecular Recognition at Serotonin Receptors . In: Science . March 2013. doi : 10.1126 / science.1232807 . PMID 23519210 .
- ↑ John R. Raymond, Justin H. Turner, Andrew K. Gelasco et al. : 5-HT Recepto Signal Transduction Pathways . In: Bryan L. Roth (Ed.): The Serotonin Receptors: From Molecular Pharmacology to Human Therapeutics . Springer, 2006, ISBN 1597450804 , pp. 143-206.
- ↑ Pytliak M, Vargová V, Mechírová V, Felšöci M: Serotonin receptors - from molecular biology to clinical applications . In: Physiol Res . 60, No. 1, 2011, pp. 15-25. PMID 20945968 .
- ↑ Kaumann AJ, Levy FO: 5-hydroxytryptamine receptors in the human cardiovascular system . In: Pharmacol. Ther. . 111, No. 3, September 2006, pp. 674-706. PMID 16960982 .
- ↑ Wacker D, Wang C, Katritch V, et al. : Structural Features for Functional Selectivity at Serotonin Receptors . In: Science . 2013. doi : 10.1126 / science.1232808 . PMID 23519215 .