HTR3A

5-hydroxytryptamine receptor 3A (5-HT-3A) is a protein, which is encoded by the HTR3A gene in humans. The product of this gene belongs to the ligand-gated ion channel receptor superfamily. It encodes a subunit of 5-hydroxytryptamine receptor 3. 5-hydroxytryptamine is a biological hormone that acts as a neurotransmitter, hormone, and mitogen. When activated, this receptor causes a rapid depolarization response in neurons.

5-hydroxytryptamine receptor 3, as a neurotransmitter in the central and peripheral nervous system, plays a role in many physiological processes, such as sleep, appetite, body temperature regulation, pain perception, hormone secretion, and sexual behavior. Abnormalities of the 5-hydroxytryptamineergic system are related to many human diseases, such as depression, migraine, epilepsy, obsessive-compulsive disorder and affective disorders. Like other neurotransmitters, 5-HT is released to synaptic junctions and acts on specific receptors on the postsynaptic membrane. Based on the binding affinity of different radioligands, several 5-HT receptors have been identified: 5-HT-1a, -1B, -1C, -1D, -2 and -3. Among them, 5-HT-3A is A subunit of the 5-HT-3 receptor. Further research shows that the 5-HT 3A receptor gene encodes 478, 487, and 483 amino acids in humans, mice, and rats, respectively. The human 5-HT 3A receptor subunit is located on chromosome 11q23.1-q23.2 and has a variety of splice variants.

5-HT 3 Receptor Function

Studies have shown that 5-HT 3 receptors belong to the Cys-loop ligand-gated ion channel receptor superfamily, similar to nicotinic acetylcholine or GABA A receptors. They exist on neurons of central and peripheral origin. After non-selective cation channels (Na⁺, K⁺ influx) are opened, they trigger rapid depolarization due to the instantaneous inward current. 5-HT 3 receptors are present in high density in certain brain areas, such as the posterior area and the nucleus of the solitary tract. At the periphery, they are located on preganglionic and postganglionic autonomic neurons and neurons of the sensory nervous system. In addition, studies have found that 5-hydroxytryptamine is involved in the regulation of cardiovascular system, exercise and intestinal secretion. In the process of intestinal secretion, 5-HT participates in various physiological functions of the gastrointestinal tract by activating 5-HT 3 receptors in the entire gastrointestinal tract.

Figure 1. The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant.

In 1991, Maricq and others cloned the mouse 5-hydroxytryptamine receptor 3A (HTR3) gene. Afterwards, Miyake et al. isolated human HTR3A cDNA from the hippocampal cDNA library. This receptor is a ligand-gated ion channel, while all other known 5-HT receptor subtypes are G protein-coupled receptors. The putative HTR3A protein contains 478 amino acids and 23 potential signal peptides. Northern blot analysis detected approximately 2.4 kb transcripts in the small intestine, colon, and brain regions (including the amygdala, hippocampus, and caudate nucleus). There are slight signals in the spleen, thymus, and prostate. Through electron microscope observation, it was found that the natural 5-HT 3 receptor in neuroblastoma-glioma cells is a pentamer. Subsequently, the scientists cloned a second subunit called 5-HT 3B. It is caused by duplication in the same site (11q23.1). Interestingly, the 5-HT 3 receptor seems to require a heteromeric combination of 5-HT 3A and 5-HT 3B subunits to provide all functional characteristics, because receptors composed of either subunit alone exhibit very low conductivity and Response amplitude.

5-HT 3 receptor antagonists are commonly used for nausea and vomiting caused by chemotherapy and radiotherapy. As 5-HT3 receptor activation in the brain leads to the release of dopamine, 5-HT3 receptor antagonists produce central effects in animal models. The effects can achieve the similar effect of antipsychotic drugs (such as dopamine receptor antagonists such as haloperidol) and anti-anxiety drugs. In addition, schizophrenia and anxiety are considered potential indications with 5-HT 3 receptor antagonists. However, there is currently no clinical data confirming this activity. Similarly, the hypothesis that 5-HT3 antagonists may prove useful in the treatment of migraine has not been realized in clinical studies. Recently, as more potential 5-HT3 receptor subunits are cloned (5-HT 3C, 3D, 3E subunits), research has become more complicated. It remains to be seen whether these 5-HT3 receptor subunits encode functional receptors or only partially inactive sequences. One hypothesis is that these subunits can act as partners. Along these lines, the co-expression of 5-HT 3A and 5-HT 3C, 3D, and 3E subunits has been confirmed in the human colon.

References

1. DanielHoyer. The 5-hydroxytryptamine System History, Neuropharmacology, and Pathology. Chapter Four - 5-hydroxytryptamine receptors nomenclature. Elsevier . 2019, Pages 63-93.
2. Maricq, A. V., et al.; Primary structure and functional expression of the 5HT-3 receptor, a 5-hydroxytryptamine-gated ion channel. Science. 1991, 254: 432-437.
3. Miyake, A., et al.; Molecular cloning of human 5-hydroxytryptamine-3 receptor: heterogeneity in distribution and function among species. Molec. Pharm. 1995, 48: 407-416.
4. Peroutka, S. J. 5-Hydroxytryptamine receptor subtypes. Annu. Rev. Neurosci. 1988, 11: 45-60.
5. Sparkes, R. S., et al.; Assignment of a 5-hydroxytryptamine 5HT-2 receptor gene (HTR2) to human chromosome 13q14-q21 and mouse chromosome 14. Genomics.1991, 9: 461-465.