Looking for a comprehensive guide to the serotonin 5-HT1B receptor? In this article, we'll give you a breakdown of everything scientists know so far about the molecular structure, physiology, and pharmacology of this serotonin receptor.
What do we know about the 5-HT1B receptor?
The 5-HT1B receptor is a G0-coupled protein receptor with seven transmembrane domains - one of which is a ligand-binding site1. Located primarily in the central nervous and vascular tissues2, there is evidence that the 5-HT1B receptor regulates a range of neurological, physiological, and pathological processes, including addiction3, migraine1, and sleep4.
5-HT1B receptors are found on the axon of presynaptic neurons in the frontal cortex, basal ganglia, and retro-medial dorsal raphe nucleus5. As their name suggests, these receptors control 5-HT (serotonin) release in serotonergic neurons, where they act as inhibitory auto-receptors2. They are also present in non-serotonergic neurons, where they act as heteroreceptors, inhibiting the release of acetylcholine, glutamate, GABA, and noradrenaline5.
Due to the range of neurotransmitters controlled by 5-HT1B, it is associated with a range of neurological functions, including mood, memory, aggression, stress sensibility, and anxiety1. The receptor is also present in the "extended amygdala" of the brain1, a reward circuit associated with drug reinforcement. It is, therefore, unsurprising that variations in the 5-HT1B gene have been associated with addiction and obsessive-compulsive disorder in humans3.
The 5-HT1B receptor is also present in the cardiovascular system, with high concentrations in the cerebral arteries6. Here 5-HT1B receptor activation leads to vasoconstriction, which may be beneficial to the treatment of migraine. Its expression in other arteries, such as coronary arteries, means that consideration must however be given to the potential for adverse cardiovascular effects such as coronary artery vasoconstriction. 5-HT1B receptors also mediate inhibition of plasma extravasation6, a process by which fluid leaks from the blood vessel into the surrounding tissues.
5-HT (serotonin) model
This assay uses subcutaneous resistance arteries to assess the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors.
What is the difference between 5-HT1B and 5-HT1D?
Not only are the 5-HT1B and 5-HT1D receptors co-expressed, but they share similar affinity for many drugs. Previously, they were thought to be the same receptor, but they are now understood to be different subtypes in humans5. There is only one known agonist that can select between 5-HT1B and 5-HT1D, and only a handful of antagonists (table 15). It is thought that therapeutics, such as anti-migraine drugs, bind to both the 5-HT1B and 5-HT1D to exert their therapeutic effects5 which has made it even more difficult to define the properties of each subtype.
|Drug||Agonist or Antagonist||5-HT1B pKB|
Table 1: A list of selective 5-HT1B drugs and their binding affinity (pKB).
What was the first therapeutically used serotonin 5-HT1 receptor agonist?
Sumatriptan (dihydroergotamine, DHE) was the first 5-HT1B agonist to be used therapeutically5. It now belongs to a wider group of drugs known as the triptans, which include almotriptan, zolmitriptan, and naratriptan6. Triptans are non-selective blockers of the 5-HT1 receptors5 that are commonly used to treat migraine. While sumatriptan has a higher affinity for the 5-HT1D subtype than 5HT1B it has a low selectivity for other receptors, making it a highly targeted 5-HT1 agonist5.
Despite these drugs being widely prescribed for migraine, it is still unclear how they exert their therapeutic effects5. So far, they are either thought to block neurogenic inflammation and nociceptive activity, or constriction-mediate 5-HT1B receptors on the cerebral arteries5 to reduce the symptoms of migraine.
5-HT (serotonin) receptors in denuded arteries
This model assesses the effect of your test article on vasoconstriction of denuded arteries via 5-HT (serotonin) receptors, in comparison to 5-HT (serotonin).
5-HT (serotonin) receptors and 5-HT
This model assesses the effect of your test article on vasoconstriction via 5-HT (serotonin) receptors, or in comparison to 5-HT (serotonin).
Are there species differences between 5HT1B/1D?
Our understanding of 5-HT1B/1D receptor function across different species has much room for progress. Despite the structure of the human 5-HT1B receptor is homologous to that in rats, differences in pharmacological response exist between rodents and humans5. These differences are thought to be caused by a single amino acid change in the transmembrane region (Thr335 is replaced by Asn in rodents) which was discovered due to differences in the binding affinity of cyanopindolol5.
However, these species differences do not only exist between animals and humans but also among closely related species. For example, 5-HT1B activation leads to hyperlocomotion in mice and hypothermia in guinea pigs but not rats5. And while there is evidence that hypophagia and penile erection are mediated by the 5-HT1B receptor in rats, this is yet to be characterized in other rodents5. Our limited knowledge of 5-HT1B receptor function across different species supports the philosophy that animal research should be reduced, refined, and replaced by more translational alternatives wherever possible.
What are the benefits of testing a 5HT1B/1D agonist in human tissue?
When the 5-HT1B agonist sumatriptan was first tested in humans, one of the volunteers experienced a cardiac event7 in response to intravenous administration. To investigate this off-target response, the researchers decided to look at the effect of teh drug on artery tone ex vivo. Using human coronary arteries, they discovered that 5-HT had a larger effect on coronary artery tone than sumatriptan7 which had a minimal effect. Researchers, therefore, decided to continue the clinical trial, and today sumatriptan is considered safe for the treatment of migraine in patients without cardiovascular contraindications7.
5-HT (serotonin) receptors and sumatriptan
This model assesses the effect of your test article on coronary artery tone using sumatriptan as a reference compound.
Where can I outsource human tissue testing for 5-HT1B agonists?
If you are looking to improve the translatability of your drug discovery research, human tissue testing allows you to look at human data before testing your compound in the clinic. It can even be used to compare drug responses between animals and humans to investigate off-target drug effects on cardiovascular tissues. At REPROCELL, our scientists can test the effects of your compound on human blood vessels. You can find examples of our work listed in our assay catalog or contact us to arrange a custom solution for your research needs.
Examples of previous studies investigating the effects of 5-HT on cardiac tissue are listed below:
- Vasoconstriction in human saphenous vein (5-HT receptor) →
- Contractile force in electrically stimulated human ventricular trabeculae muscle (5-HT receptor) →
- Contractile force in electrically stimulated human atrial pectinate muscle (5-HT receptor)→
- Sari Y et al. The Brain as a Drug Target. Progress in Molecular Biology and Translational Science 98 pp 401-433 (2011).
- Sharma H.S. Influence of Serotonin on the Blood-Brain and the Blood-Spinal Cord Barriers. Blood and Spinal Cord Barriers in Health and Disease (2004).
- Meneses A. 5-HT1B Receptor. The Role of 5-HT Systems on Memory and Dysfunctional Memory (2014).
- Nonogaki K. Sleep Hormones. Vitamins and Hormones 89 pp 1-17 (2012).
- Blackburn T.P. Serotonin (5-Hydroxytryptamine; 5-HT): Receptors. Encyclopedia of Neuroscience (2009).
- Hoyer D. 5-HT-1B Receptor. xPharm: The Comprehensive Pharmacology Reference (2007).
- Tansey EM & Yabsley A. Humphrey, Patrick: 04 - Sumatriptan: safety issues. History of Modern Biomedicine Interviews (Digital Collection) Item e2016025 (2016)