5-HT5A receptor explained

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene.^{[1] [2]} Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.

Function

The gene described in this record is a member of 5-hydroxytryptamine receptor family and encodes a multi-pass membrane protein that functions as a receptor for 5-hydroxytryptamine and couples to G proteins, negatively influencing cAMP levels via G_i and G_o.^[3] This protein has been shown to function in part through the regulation of intracellular Ca²⁺ mobilization.^[1] The 5-HT_5A receptor has been shown to be functional in a native expression system.^[4]

Rodents have been shown to possess two functional 5-HT₅ receptor subtypes, 5-HT_5A and 5-HT_5B,^[5] however while humans possess a gene coding for the 5-HT_5B subtype, its coding sequence is interrupted by stop codons, making the gene non-functional, and so only the 5-HT_5A subtype is expressed in human brain.^[6]

It also appears to serve as a presynaptic serotonin autoreceptor.^[7]

Clinical significance

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in a wide range of psychiatric conditions and also has vasoconstrictive and vasodilatory effects.^[1]

Selective ligands

Few highly selective ligands are commercially available for the 5-HT_5A receptor. When selective activation of this receptor is desired in scientific research, the non-selective serotonin receptor agonist 5-Carboxamidotryptamine can be used in conjunction with selective antagonists for its other targets (principally 5-HT_1A, 5-HT_1B, 5-HT_1D, and 5-HT₇). Research in this area is ongoing.^{[8] [9]}

Agonists

• LSD:(+)-lysergic acid.^{[10] [11]}
• Lisuride partial agonist.
• 5-CT full agonist.
• Methylergometrine full agonist.
• Valerenic acid a component of valerian, has been shown to act as a 5HT_5A partial agonist.^[12]
• Olanzapine an atypical antipsychotic.^[13]
• Psilocin^[14]
• Another ligand that has been recently disclosed is shown below, claimed be a selective 5-HT_5A agonist with K_i = 124 nM.^[15]

Antagonists

• ASP-5736^{[16] [17]}
• AS-2030680^[16]
• AS-2674723^[16]
• MS112 selective potent antangonist.
• Latrepirdine (non-selective).^[18]
• Risperidone (non-selective), moderate 206 nM affinity.
• SB-699,551

See also

• 5-HT receptor
• 5-HT₁ receptor
• 5-HT₂ receptor
• 5-HT₃ receptor
• 5-HT₄ receptor
• 5-HT₆ receptor
• 5-HT₇ receptor

Further reading

• Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, Grewal JS, Garnovskaya MN . 6 . Multiplicity of mechanisms of serotonin receptor signal transduction . Pharmacology & Therapeutics . 92 . 2–3 . 179–212 . 2002 . 11916537 . 10.1016/S0163-7258(01)00169-3 .
• Thomas DR . 5-ht5A receptors as a therapeutic target . Pharmacology & Therapeutics . 111 . 3 . 707–714 . September 2006 . 16516972 . 10.1016/j.pharmthera.2005.12.006 .
• Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M . Cloning and characterisation of the human 5-HT5A serotonin receptor . FEBS Letters . 355 . 3 . 242–246 . December 1994 . 7988681 . 10.1016/0014-5793(94)01209-1 . 36425845 . free .
• Schanen NC, Scherer SW, Tsui LC, Francke U . Assignment of the 5-hydroxytryptamine (serotonin) receptor 5A gene (HTR5A) to human chromosome band 7q36.1 . Cytogenetics and Cell Genetics . 72 . 2–3 . 187–188 . 1997 . 8978771 . 10.1159/000134184 . free . 10722/42533 .
• Toward a complete human genome sequence . Genome Research . 8 . 11 . 1097–1108 . November 1998 . 9847074 . 10.1101/gr.8.11.1097 . free . The Washington University Genome Sequencing Cente . The Sanger Centre .
• Francken BJ, Josson K, Lijnen P, Jurzak M, Luyten WH, Leysen JE . Human 5-hydroxytryptamine(5A) receptors activate coexpressed G(i) and G(o) proteins in Spodoptera frugiperda 9 cells . Molecular Pharmacology . 57 . 5 . 1034–1044 . May 2000 . 10779389 .
• Marazziti D, Ori M, Nardini M, Rossi A, Nardi I, Cassano GB . mRNA expression of serotonin receptors of type 2C and 5A in human resting lymphocytes . Neuropsychobiology . 43 . 3 . 123–126 . 2001 . 11287788 . 10.1159/000054878 . 20724896 .
• Iwata N, Ozaki N, Inada T, Goldman D . Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia . Molecular Psychiatry . 6 . 2 . 217–219 . March 2001 . 11317225 . 10.1038/sj.mp.4000829 . free .
• Grailhe R, Grabtree GW, Hen R . Human 5-HT(5) receptors: the 5-HT(5A) receptor is functional but the 5-HT(5B) receptor was lost during mammalian evolution . European Journal of Pharmacology . 418 . 3 . 157–167 . April 2001 . 11343685 . 10.1016/S0014-2999(01)00933-5 .
• Noda M, Yasuda S, Okada M, Higashida H, Shimada A, Iwata N, Ozaki N, Nishikawa K, Shirasawa S, Uchida M, Aoki S, Wada K . 6 . Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways . Journal of Neurochemistry . 84 . 2 . 222–232 . January 2003 . 12558985 . 10.1046/j.1471-4159.2003.01518.x . 7364018 . free .
• Khorana N, Smith C, Herrick-Davis K, Purohit A, Teitler M, Grella B, Dukat M, Glennon RA . 6 . Binding of tetrahydrocarboline derivatives at human 5-HT5A receptors . Journal of Medicinal Chemistry . 46 . 18 . 3930–3937 . August 2003 . 12930153 . 10.1021/jm030080s .
• Dietz BM, Mahady GB, Pauli GF, Farnsworth NR . Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro . Brain Research. Molecular Brain Research . 138 . 2 . 191–197 . August 2005 . 15921820 . 5805132 . 10.1016/j.molbrainres.2005.04.009 .

External links

• Web site: 5-ht_5a . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Web site: Entrez Gene: HTR5A 5-hydroxytryptamine (serotonin) receptor 5A.
2. Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M . Cloning and characterisation of the human 5-HT5A serotonin receptor . FEBS Letters . 355 . 3 . 242–246 . December 1994 . 7988681 . 10.1016/0014-5793(94)01209-1 . 36425845 . free .
3. Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE . The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells . European Journal of Pharmacology . 361 . 2–3 . 299–309 . November 1998 . 9865521 . 10.1016/S0014-2999(98)00744-4 .
4. Goodfellow NM, Bailey CD, Lambe EK . The native serotonin 5-HT(5A) receptor: electrophysiological characterization in rodent cortex and 5-HT(1A)-mediated compensatory plasticity in the knock-out mouse . The Journal of Neuroscience . 32 . 17 . 5804–5809 . April 2012 . 22539842 . 4644074 . 10.1523/JNEUROSCI.4849-11.2012 .
5. Matthes H, Boschert U, Amlaiky N, Grailhe R, Plassat JL, Muscatelli F, Mattei MG, Hen R . 6 . Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization . Molecular Pharmacology . 43 . 3 . 313–319 . March 1993 . 8450829 .
6. Nelson DL . 5-HT5 receptors . Current Drug Targets. CNS and Neurological Disorders . 3 . 1 . 53–58 . February 2004 . 14965244 . 10.2174/1568007043482606 .
7. Thomas DR, Soffin EM, Roberts C, Kew JN, de la Flor RM, Dawson LA, Fry VA, Coggon SA, Faedo S, Hayes PD, Corbett DF, Davies CH, Hagan JJ . 6 . SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain . Neuropharmacology . 51 . 3 . 566–577 . September 2006 . 16846620 . 10.1016/j.neuropharm.2006.04.019 . 543423 .
8. Wesołowska A . In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors . Polish Journal of Pharmacology . 54 . 4 . 327–341 . 2002 . 12523486 .
9. Peters JU, Lübbers T, Alanine A, Kolczewski S, Blasco F, Steward L . Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration . Bioorganic & Medicinal Chemistry Letters . 18 . 1 . 262–266 . January 2008 . 18023344 . 10.1016/j.bmcl.2007.10.078 .
10. The RBI Handbook of Receptor Classification and Signal Transduction, page 114 (1995)
11. Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL . 6 . Inactive and active state structures template selective tools for the human 5-HT_5A receptor . Nature Structural & Molecular Biology . 29 . 7 . 677–687 . July 2022 . 35835867 . 9299520 . 10.1038/s41594-022-00796-6 .
12. Dietz BM, Mahady GB, Pauli GF, Farnsworth NR . Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro . Brain Research. Molecular Brain Research . 138 . 2 . 191–197 . August 2005 . 15921820 . 5805132 . 10.1016/j.molbrainres.2005.04.009 .
13. [Bryan Roth|Roth BL]
14. Ray TS . Psychedelics and the human receptorome . PLOS ONE . 5 . 2 . e9019 . February 2010 . 20126400 . 2814854 . 10.1371/journal.pone.0009019 . free . 2010PLoSO...5.9019R .
15. Garcia-Ladona FJ, Szabo L, Steiner G, Hofmann HP . 2004-06-15 . Use of 5-HT5-ligands in the treatment of neurodegenerative and neuropsychiatric disturbances . US . 6750221.
16. Yamazaki M, Okabe M, Yamamoto N, Yarimizu J, Harada K . Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats . Journal of Pharmacological Sciences . 127 . 3 . 362–369 . March 2015 . 25837935 . 10.1016/j.jphs.2015.02.006 . free .
17. Yamazaki M, Harada K, Yamamoto N, Yarimizu J, Okabe M, Shimada T, Ni K, Matsuoka N . 6 . ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia . European Neuropsychopharmacology . 24 . 10 . 1698–1708 . October 2014 . 25108314 . 10.1016/j.euroneuro.2014.07.009 . free .
18. Wu J, Li Q, Bezprozvanny I . Evaluation of Dimebon in cellular model of Huntington's disease . Molecular Neurodegeneration . 3 . 1 . 15 . October 2008 . 18939977 . 2577671 . 10.1186/1750-1326-3-15 . free .