5-HT receptor

from Wikipedia, the free encyclopedia

Serotonin (also 5-hydroxytryptamine, 5-HT ) mediates its physiological and pathophysiological effects through the activation of various receptors bound to the cell membrane , the 5-HT receptors (also serotonin receptors ). These are found in high density in the central nervous system , the gastrointestinal tract , the cardiovascular system and the blood . Physiologically they play u. a. play a role in blood clotting , learning processes and the control of the day-night rhythm. Of pathological significance is a dysregulation of biochemical processes at the serotonin receptors in migraine , pulmonary hypertension , depression , schizophrenia , eating disorders , nausea and vomiting .

In humans, a distinction can currently be made between at least 14 different 5-HT receptors, which are grouped into 7 families: 5-HT 1 to 5-HT 7 . With the exception of the 5-HT 3 receptors, which form ion channels , all 5-HT receptors are G protein-coupled receptors . Around 70 different serotonin receptors had been cloned from animal species, including invertebrates , by the turn of the millennium.

Systematics of the 5-HT receptors

5-HT 1 receptors

The 5-HT 1 receptors with 5 subtypes (A, B, D, E and F) represent the largest group of 5-HT receptors. Characteristic of these receptors is that they are not only caused by 5-HT but also by 5- Carboxamidotryptamine (5-CT) are activated and lead to an inhibition of adenylyl cyclase via G i / G o proteins .

  • Both pre- and postsynaptic 5-HT 1A receptors are responsible in the central nervous system for learning processes, for regulating body temperature, central blood pressure regulation and for signal transmission. The 5-HT 1A receptor is also of pharmacological interest as a target structure for the treatment of central nervous disorders (for example anxiety and depression). It has been shown that depression and anxiety disorders have a reduced density of this type of receptor in certain areas of the brain. The 5-HT 1A receptor agonist buspirone is used therapeutically as an anxiolytic .
  • 5-HT 1B - and 5-HT 1D receptors are two very similar receptors. In the central nervous system (5-HT 1B / 1D ), for example, they suppress theneuronal inflammatory processes triggeredby migraines . For this reason, 5-HT 1B / 1D receptor agonists such as ergotamine or the newer triptans (for example sumatriptan ) were developed as drugs to stop migraine attacks. In addition, the activation of 5-HT 1B receptorsfound on blood vessels appears tobe responsible for both the migraine efficacy and the cardiovascular side effects of these drugs.
  • The 5-HT 1F receptor , like the 5-HT 1B / 1D receptor, is involved in the suppression of neuronal inflammation and is therefore a novel target for the development of migraine drugs.

5-HT 2 receptors

The 5-HT 2 receptors are divided into subtypes A, B and C. They are activated by α-methyl-5-HT and mediate their effects via G q / 11 protein-coupled receptors.

  • The 5-HT 2B receptors, which predominantly occur in blood vessels, are associated with diseases such as migraines and chronic hypertension. Heart valve damage and primary pulmonary hypertension as severe side effects as a result of taking the anti- Parkinsonian drug pergolide or the obsolete appetite suppressants fenfluramine and aminorex are also attributed to activation of 5-HT 2B receptors.
  • The 5-HT 2C receptor , on the other hand, is only found in the central nervous system. It is associated with the regulation of eating and sexual behavior. The appetite-suppressing effect of fenfluramine and the US-approved Lorcaserin is based on the activation of 5-HT 2C receptors.

Antidepressants mediate their long-term action (from about 2 weeks of treatment period), inter alia, via a down-regulation of post-synaptic 5-HT 2A receptors and adrenergic β receptors . The thus reduced signaling effect of the 5-HT 2A receptors is significantly involved in the anxiolytic effect of the antidepressants. Inhibition of the responsiveness of presynaptic 5-HT 1 - autoreceptors leads out above in an increased release of 5-HT in the synaptic cleft.

5-HT 3 receptors

As a ligand-controlled ion channel, the 5-HT 3 receptor occupies a unique position among the 5-HT receptors. It consists of five protein molecules and is selective for the passage of sodium and potassium ions . This receptor, which occurs exclusively on central and peripheral neurons, is responsible, among other things, for triggering the vomiting reflex. 5-HT 3 receptor antagonists such as ondansetron , palonosetron and tropisetron are thus used highly effectively to suppress vomiting induced by cytotoxic drugs .

5-HT 4 receptors

The G s protein-coupled 5-HT 4 receptor is of particular importance in the gastrointestinal tract, but also on the heart . It regulates intestinal activity through the release of acetylcholine . The 5-HT 4 receptor agonist cisapride was used as a prokinetic for a while until it was withdrawn from the market for causing cardiac arrhythmias . This resulted in QT prolongation in the ECG . Another prokinetically active 5-HT 4 receptor agonist, tegaserod , was approved for the treatment of irritable bowel syndrome in the USA and Switzerland , but was withdrawn from the market in 2007 because of cardiac side effects. Prucalopride (trade name Resolor ) has been approved in the EU and Switzerland since 2010 for the treatment of idiopathic chronic constipation in women and is not supposed to be proarrhythmic. In June 2015, the manufacturer Shire received EU approval for men as well.

"Higher" 5-HT receptors (5-HT 5 , 5-HT 6 and 5-HT 7 )

This group includes newer 5-HT receptors (discovered since 1992) that differ significantly from other 5-HT receptors in molecular biology. With the exception of the 5-HT 7 receptor, little is known about their functional significance , which is expressed in the nomenclature by using small letters.

5-HT 5 receptors with their subtypes A and B lead to an inhibition of adenylyl cyclase.

  • The 5-HT 5A receptor is possibly involved in the circadian rhythm.
  • The 5-HT 5B receptor in humans is a pseudogene and thus a receptor that is not expressed. Its coding DNA sequence is interrupted by stop codons .

The only centrally occurring G s protein-coupled 5-HT 6 receptor can possibly be associated with learning processes. Atypical neuroleptics (for example clozapine) also show a high affinity for this receptor.

The ubiquitous (everywhere) occurring 5-HT 7 receptor has been investigated much better . In addition to regulating the day-night rhythm and body temperature, it is responsible for the long-lasting lowering of blood pressure through 5-HT. Both typical ( e.g. pimozide ) and atypical antipsychotics ( e.g. clozapine ) show a high affinity for this receptor.

See also

literature

  • Hoyer D, Clarke DE, Fozard JR, et al. : International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin) . In: Pharmacol. Rev. . 46, No. 2, June 1994, pp. 157-203. PMID 7938165 .
  • Saudou F, Hen R: 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates . In: Neurochem. Int. . 25, No. 6, December 1994, pp. 503-32. PMID 7894328 .
  • Hen R: Structural and functional conservation of serotonin receptors throughout evolution . In: EXS . 63, 1993, pp. 266-78. PMID 8422538 .

Web links

Individual evidence

  1. ↑ Hoyer D, Clarke DE, Fozard JR, et al. : International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin) . In: Pharmacol. Rev. . 46, No. 2, June 1994, pp. 157-203. PMID 7938165 .
  2. ↑ Kroeze WK, Roth BL: The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis . In: Biol. Psychiatry . 44, No. 11, 1998, pp. 1128-42. PMID 9836016 .
  3. ^ Pain Clinic Kiel: Migraine Knowledge - Seizure Treatment
  4. ↑ Ramadan NM, Skljarevski V, Phebus LA, Johnson KW: 5-HT1F receptor agonists in acute migraine treatment: a hypothesis . In: Cephalalgia . 23, No. 8, October 2003, pp. 776-785. PMID 14510923 .
  5. ↑ Klaus Helm: Synthesis and functional in vitro pharmacology of new ligands of the 5-HT 2 A receptor from the tryptamine class. Dissertation, University of Regensburg 2014
  6. ↑ Roth BL: Drugs and valvular heart disease . In: N. Engl. J. Med. . 356, No. 1, January 2007, pp. 6-9. doi : 10.1056 / NEJMp068265 . PMID 17202450 .
  7. ↑ Launay JM, Hervé P, Peoc'h K, et al. : Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension . In: Nat. Med. . 8, No. 10, October 2002, pp. 1129-35. doi : 10.1038 / nm764 . PMID 12244304 .
  8. ↑ Bays HE: Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for 'sick fat' and metabolic disease . In: Expert Rev Cardiovasc Ther . 7, No. 11, November 2009, pp. 1429-1445. doi : 10.1586 / erc.09.123 . PMID 19900026 .
  9. ↑ Curzon G, Gibson EL, Oluyomi AO: Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability . In: Trends Pharmacol. Sci. . 18, No. 1, January 1997, pp. 21-5. PMID 9114726 .
  10. ↑ Aktories, Förstermann, Hofmann, Starke: General and special pharmacology and toxicology , 10th edition 2009, Elsevier Verlag.
  11. ↑ Shire Receives European Approval to Use Resolor® (prucalopride) in Men for the Symptomatic Treatment of Chronic Constipation , PM by Shire, June 3, 2015.
  12. ↑ Nelson DL: 5-HT5 receptors . In: Curr Drug Targets CNS Neurol Disord . 3, No. 1, February 2004, pp. 53-58. PMID 14965244 .
  13. ↑ Roth BL, Craigo SC, Choudhary MS, et al. : Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 ​​and 5-hydroxytryptamine-7 receptors . In: J. Pharmacol. Exp. Ther. . 268, No. 3, March 1994, pp. 1403-10. PMID 7908055 .