ReproCELL Incorporated : Everything we know about the 5HT1B receptor

Looking for a comprehensive guide to the serotonin 5HT1B receptor? In this article, we'll give you a breakdown of everything scientists know so far about its molecular structure, physiology, and pharmacology.

What do we know about the 5 HT 1B receptor?

The 5HT1B receptor is a G₀-coupled protein receptor with seven transmembrane domains - one of which is a ligand-binding site. Located primarily in the central nervous and vascular tissues, there is evidence that the 5HT1B receptor regulates a range of neurological, physiological, and pathological processes, including addiction, migraine, and sleep.

5HT1B receptors are found on the axon of presynaptic neurons in the frontal cortex, basal ganglia, and retro-medial dorsal raphe nucleus. As their name suggests, these receptors control 5HT (serotonin) release in serotonergic neurons, where they act as inhibitory auto-receptors. They are also present in non-serotonergic neurons, where they act as heteroreceptors, inhibiting the release of acetylcholine, glutamate, GABA, and noradrenaline.

Due to the range of neurotransmitters controlled by 5HT1B, it is associated with a range of neurological functions, including mood, memory, aggression, stress sensibility, and anxiety. The receptor is also present in the "extended amygdala" of the brain, a reward circuit associated with drug reinforcement. It is, therefore, unsurprising that variations in the 5HT1B gene have been associated with addiction and obsessive-compulsive disorder in humans.

The 5HT1B receptor is also present in the cardiovascular system, with high concentrations in the cerebral arteries. 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 extravasation, a process by which fluid leaks from the blood vessel into the surrounding tissues.

What is the difference between 5HT1B and 5HT1D?

Not only are the 5HT1B and 5HT1D 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 humans. There is only one known agonist that can select between 5HT1B and 5HT1D, and only a handful of agonists (table 1). It is thought that therapeutics, such as anti-migraine drugs, bind to both the 5-HT1B and 5-HT1D to exert their therapeutic effects which has made it even more difficult to define the properties of each subtype.

Drug	Agonist or Antagonist	5-HT1B pKB
L694247	Agonist	10.0
GR55562	Antagonist	7.4
SB224289	Antagonist	8.5
SB236657	Antagonist	8.9
SB236057	Antagonist	8.9

Table 1: A list of selective 5-HT1B drugs and their binding affinity (pK_B).

What was the first therapeutically used serotonin 5HT 1 receptor agonist?

Sumatriptan (dihydroergotamine, DHE) was the first 5HT1B agonist to be used therapeutically. It now belongs to a wider group of drugs known as the Triptans, which include almotriptan, zolmitriptan, and naratriptan. Triptans are non-selective blockers of the 5HT1 receptors that are commonly used to treat migraine. While Sumatriptan has a higher affinity for the 5HT1D subtype than 5HT1B it has a low selectivity for other receptors, making it a highly targeted 5HT1 agonist.

Despite these drugs being widely prescribed for migraine, it is still unclear how they exert their therapeutic effects. So far, they are either thought to block neurogenic inflammation and nociceptive activity, or constriction-mediate 5-HT1B receptors on the cerebral arteries < /a>to reduce the symptoms of migraine.

Are there species differences between 5HT1B 1D?

Our understanding of 5HT1B/1D receptor function across different species has much room for progress. Despite the structure of the human 5HT1B receptor is homologous to that in rats, differences in pharmacological response exist between rodents and humans. 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 cyanopindolol.

However, these species differences do not only exist between animals and humans but also among closely related species. For example, 5HT1B activation leads to hyperlocomotion in mice and hypothermia in guinea pigs but not rats. And while there is evidence that hypophagia and penile erection are mediated by the 5HT1B receptor in rats, this is yet to be characterized in other rodents. Our limited knowledge of 5HT1B 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 5HT1B agonist sumatriptan was first tested in humans, one of the volunteers experienced a cardiac event in response to intravenous administration. To investigate this off-target response, the researchers decided to look at the effect of Sumatriptan on artery tone ex vivo. Using human coronary arteries, they discovered that 5-HT had a larger effect on coronary artery tone than sumatriptan 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 contraindications. You can hear more from Professor Humphrey, who contributed to the development of the drug, in the YouTube video below.

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 our previous studies investigating the effects of 5-HT on blood vessel activity are listed below:

References

1. Sari Y et al. The Brain as a Drug Target. Progress in Molecular Biology and Translational Science98 pp 401-433 (2011).
2. Blackburn T.P. Serotonin (5-Hydroxytryptamine; 5-HT): Receptors. Encyclopedia of Neuroscience(2009).
3. Nonogaki K. Sleep Hormones. Vitamins and Hormones 89 pp 1-17 (2012).
4. 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).
5. Meneses A. 5-HT1B Receptor. The Role of 5-HT Systems on Memory and Dysfunctional Memory(2014).
6. Hoyer D. 5-HT-1B Receptor. xPharm: The Comprehensive Pharmacology Reference(2007).
7. Tansey EM & Yabsley A. Humphrey, Patrick: 04 - Sumatriptan: safety issues.History of Modern Biomedicine Interviews (Digital Collection)Item e2016025 (2016)