5-HT1E receptor explained

5-hydroxytryptamine (serotonin) 1E receptor (5-HT_1E) is a highly expressed human G-protein coupled receptor^[1] that belongs to the 5-HT1 receptor family (G_i-coupled serotonin receptor).^{[2] [3]} The human gene is denoted as HTR1E.^[4]

Function

The function of the 5-HT_1E receptor is unknown due to the lack of selective pharmacological tools, specific antibodies, and permissive animal models.^[5] The 5-HT_1E receptor gene lacks polymorphisms amongst humans (few mutations), indicating a high degree of evolutionary conservation of genetic sequence, which suggests that the 5-HT_1E receptor has an important physiological role in humans.^[6] It is hypothesized that the 5-HT_1E receptor is involved in the regulation of memory in humans due to the high abundance of receptors in the frontal cortex, hippocampus, and olfactory bulb, all of which are regions of the brain integral to memory regulation.^[7]

This receptor is unique among the serotonin receptors in that it is not known to be expressed by rats or mouse species, all of which lack the gene encoding the 5-HT_1E receptor. However the genomes of the pig, rhesus monkey, and several lagomorphs (including rabbit) as well as the guinea pig each encode a homologous 5-HT_1E receptor gene.^[7] The guinea pig is the most likely candidate for future study of 5-HT_1E receptor function in vivo. The expression of 5-HT_1E receptors in the guinea pig brain has been pharmacologically confirmed; 5-HT_1E receptor expression patterns of the human and guinea pig brains appear to be similar.^[5] In the human cortex, the expression of 5-HT_1E undergoes a marked transition during adolescence, in a way that is strongly correlated with the expression of 5-HT_1B.^[8]

The most closely related receptor to the 5-HT_1E is the 5-HT_1F receptor. They share 57% amino acid sequence homology and have some pharmacological characteristics in common.^[9] Both receptors are G_i-coupled (inhibit adenylate cyclase activity) and both receptors have high affinities for 5-HT and low affinities for 5-carboxyamidotryptaine and mesulergine.^[10] However, due to major differences in brain expression patterns, these receptors are unlikely to mediate similar functions in humans. For example, 5-HT_1E receptors are abundant in the hippocampus but are not detectable in the striatum (caudate and putamen of the human brain), while the opposite is true for the 5-HT_1F receptor. Thus, conclusions about the function of the 5-HT_1E receptor cannot be ascribed to the function of the 5-HT_1F receptor, and vice versa.^[5]

Selective ligands

No highly selective 5-HT_1E ligands are available yet. [³H]5-HT remains the only radioligand available with high affinity for the 5-HT_1E receptor (5nM).

Agonists

• BRL-54443 (5-Hydroxy-3-(1-methylpiperidin-4-yl)-1H-indole) - mixed 5-HT_1E/1F agonist

Antagonists

None as yet.

See also

• 5-HT₁ receptor
• 5-HT receptor

Further reading

• Zgombick JM, Schechter LE, Macchi M, Hartig PR, Branchek TA, Weinshank RL . Human gene S31 encodes the pharmacologically defined serotonin 5-hydroxytryptamine1E receptor . Molecular Pharmacology . 42 . 2 . 180–5 . Aug 1992 . 1513320 .
• McAllister G, Charlesworth A, Snodin C, Beer MS, Noble AJ, Middlemiss DN, Iversen LL, Whiting P . Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype . Proceedings of the National Academy of Sciences of the United States of America . 89 . 12 . 5517–21 . Jun 1992 . 1608964 . 49323 . 10.1073/pnas.89.12.5517 . 1992PNAS...89.5517M . free .
• Levy FO, Gudermann T, Birnbaumer M, Kaumann AJ, Birnbaumer L . Molecular cloning of a human gene (S31) encoding a novel serotonin receptor mediating inhibition of adenylyl cyclase . FEBS Letters . 296 . 2 . 201–6 . Jan 1992 . 1733778 . 10.1016/0014-5793(92)80379-U . 5557457 . free .
• Levy FO, Holtgreve-Grez H, Taskén K, Solberg R, Ried T, Gudermann T . Assignment of the gene encoding the 5-HT1E serotonin receptor (S31) (locus HTR1E) to human chromosome 6q14-q15 . Genomics . 22 . 3 . 637–40 . Aug 1994 . 8001977 . 10.1006/geno.1994.1439 .
• Pierce PA, Xie GX, Meuser T, Peroutka SJ . 5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study . Neuroscience . 81 . 3 . 813–9 . Dec 1997 . 9316030 . 10.1016/S0306-4522(97)00235-2 . 962014 .

Notes and References

1. Leonhardt S, Herrick-Davis K, Titeler M . Detection of a novel serotonin receptor subtype (5-HT1E) in human brain: interaction with a GTP-binding protein . Journal of Neurochemistry . 53 . 2 . 465–71 . Aug 1989 . 2664084 . 10.1111/j.1471-4159.1989.tb07357.x . 43594695 .
2. McAllister G, Charlesworth A, Snodin C, Beer MS, Noble AJ, Middlemiss DN, Iversen LL, Whiting P . Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype . Proceedings of the National Academy of Sciences of the United States of America . 89 . 12 . 5517–21 . Jun 1992 . 1608964 . 49323 . 10.1073/pnas.89.12.5517 . 1992PNAS...89.5517M . free .
3. Levy FO, Holtgreve-Grez H, Taskén K, Solberg R, Ried T, Gudermann T . Assignment of the gene encoding the 5-HT1E serotonin receptor (S31) (locus HTR1E) to human chromosome 6q14-q15 . Genomics . 22 . 3 . 637–40 . Aug 1994 . 8001977 . 10.1006/geno.1994.1439 .
4. Web site: Entrez Gene: HTR1E 5-hydroxytryptamine (serotonin) receptor 1E.
5. Klein MT, Teitler M . Guinea pig hippocampal 5-HT(1E) receptors: a tool for selective drug development . Journal of Neurochemistry . 109 . 1 . 268–74 . Apr 2009 . 19200348 . 2827198 . 10.1111/j.1471-4159.2009.05958.x .
6. Shimron-Abarbanell D, Nöthen MM, Erdmann J, Propping P . Peter Propping . Lack of genetically determined structural variants of the human serotonin-1E (5-HT1E) receptor protein points to its evolutionary conservation . Brain Research. Molecular Brain Research . 29 . 2 . 387–90 . Apr 1995 . 7609628 . 10.1016/0169-328X(95)00003-B .
7. Bai F, Yin T, Johnstone EM, Su C, Varga G, Little SP, Nelson DL . Molecular cloning and pharmacological characterization of the guinea pig 5-HT1E receptor . European Journal of Pharmacology . 484 . 2–3 . 127–39 . Jan 2004 . 14744596 . 10.1016/j.ejphar.2003.11.019 .
8. Shoval G, Bar-Shira O, Zalsman G, John Mann J, Chechik G . Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence . European Neuropsychopharmacology . 24 . 7 . 1123–32 . Jul 2014 . 24721318 . 10.1016/j.euroneuro.2014.02.009 . 14534307 .
9. Barnes NM, Sharp T . A review of central 5-HT receptors and their function . Neuropharmacology . 38 . 8 . 1083–152 . Aug 1999 . 10462127 . 10.1016/S0028-3908(99)00010-6 . 5930124 .
10. Adham N, Kao HT, Schecter LE, Bard J, Olsen M, Urquhart D, Durkin M, Hartig PR, Weinshank RL, Branchek TA . Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase . Proceedings of the National Academy of Sciences of the United States of America . 90 . 2 . 408–12 . Jan 1993 . 8380639 . 45671 . 10.1073/pnas.90.2.408 . 1993PNAS...90..408A . free .