5-HT5A receptor

5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene.^[5][6] 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.

HTR5A
Identifiers
Aliases	HTR5A, 5-HT5A, 5-HT5A receptor, 5-hydroxytryptamine receptor 5A
External IDs	OMIM: 601305; MGI: 96283; HomoloGene: 22461; GeneCards: HTR5A; OMA:HTR5A - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q36.2 Start 155,070,324 bp[1] End 155,087,392 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 B1|5 13.24 cM Start 28,047,147 bp[2] End 28,060,086 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in cerebellar hemisphere right hemisphere of cerebellum prefrontal cortex right frontal lobe Brodmann area 9 anterior cingulate cortex secondary oocyte Hypothalamus nucleus accumbens superior frontal gyrus Top expressed in secondary oocyte intestinal villus Ileal epithelium zygote lumbar subsegment of spinal cord choroid plexus of fourth ventricle perirhinal cortex entorhinal cortex gastrula primary visual cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity G protein-coupled serotonin receptor activity neurotransmitter receptor activity serotonin binding Cellular component integral component of membrane perikaryon plasma membrane rough endoplasmic reticulum Golgi apparatus integral component of plasma membrane membrane dendrite integral component of postsynaptic specialization membrane Biological process G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger brain development response to estradiol hippocampus development cAMP-mediated signaling signal transduction adenylate cyclase-inhibiting serotonin receptor signaling pathway chemical synaptic transmission Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3361 15563 Ensembl ENSG00000157219 ENSMUSG00000039106 UniProt P47898 P30966 RefSeq (mRNA) NM_024012 NM_008314 RefSeq (protein) NP_076917 NP_032340 Location (UCSC) Chr 7: 155.07 – 155.09 Mb Chr 5: 28.05 – 28.06 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7] This protein has been shown to function in part through the regulation of intracellular Ca²⁺ mobilization.^[5] The 5-HT_5A receptor has been shown to be functional in a native expression system.^[8]

Rodents have been shown to possess two functional 5-HT₅ receptor subtypes, 5-HT_5A and 5-HT_5B,^[9] 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.^[10]

It also appears to serve as a presynaptic serotonin autoreceptor.^[11]

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.^[5]

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.^[12][13]

Agonists

• LSD:(+)-lysergic acid.^[14][15]
• Lisuride – partial agonist.^[15]
• 5-CT – full agonist.^[15]
• Methylergometrine – full agonist.^[15]
• Valerenic acid – a component of valerian, has been shown to act as a 5HT_5A partial agonist.^[16]
• Olanzapine – an atypical antipsychotic.^[17]
• Psilocin^[18]
• Aripiprazole - an atypical antipsychotic
• Mirtazapine - an atypical antidepressant
• Another ligand that has been recently disclosed is shown below, claimed be a selective 5-HT_5A agonist with K_i = 124 nM.^[19]

Antagonists

• ASP-5736^[20][21]
• AS-2030680^[20]
• AS-2674723^[20]
• MS112 – selective potent antangonist.^[15]
• Latrepirdine (non-selective).^[22]
• 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

References

1. GRCh38: Ensembl release 89: ENSG00000157219 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000039106 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: HTR5A 5-hydroxytryptamine (serotonin) receptor 5A".
6. Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M (December 1994). "Cloning and characterisation of the human 5-HT5A serotonin receptor". FEBS Letters. 355 (3): 242–246. doi:10.1016/0014-5793(94)01209-1. PMID 7988681. S2CID 36425845.
7. Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE (November 1998). "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. doi:10.1016/S0014-2999(98)00744-4. PMID 9865521.
8. Goodfellow NM, Bailey CD, Lambe EK (April 2012). "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. doi:10.1523/JNEUROSCI.4849-11.2012. PMC 4644074. PMID 22539842.
9. Matthes H, Boschert U, Amlaiky N, Grailhe R, Plassat JL, Muscatelli F, et al. (March 1993). "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. PMID 8450829.
10. Nelson DL (February 2004). "5-HT5 receptors". Current Drug Targets. CNS and Neurological Disorders. 3 (1): 53–58. doi:10.2174/1568007043482606. PMID 14965244.
11. Thomas DR, Soffin EM, Roberts C, Kew JN, de la Flor RM, Dawson LA, et al. (September 2006). "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. doi:10.1016/j.neuropharm.2006.04.019. PMID 16846620. S2CID 543423.
12. Wesołowska A (2002). "In the search for selective ligands of 5-HT5, 5-HT6 and 5-HT7 serotonin receptors" (PDF). Polish Journal of Pharmacology. 54 (4): 327–341. PMID 12523486.
13. Peters JU, Lübbers T, Alanine A, Kolczewski S, Blasco F, Steward L (January 2008). "Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration". Bioorganic & Medicinal Chemistry Letters. 18 (1): 262–266. doi:10.1016/j.bmcl.2007.10.078. PMID 18023344.
14. The RBI Handbook of Receptor Classification and Signal Transduction, page 114 (1995)ISBN 0-9640548-1-7
15. Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, et al. (July 2022). "Inactive and active state structures template selective tools for the human 5-HT_5A receptor". Nature Structural & Molecular Biology. 29 (7): 677–687. doi:10.1038/s41594-022-00796-6. PMC 9299520. PMID 35835867.
16. Dietz BM, Mahady GB, Pauli GF, Farnsworth NR (August 2005). "Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro". Brain Research. Molecular Brain Research. 138 (2): 191–197. doi:10.1016/j.molbrainres.2005.04.009. PMC 5805132. PMID 15921820.
17. Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
18. Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2): e9019. Bibcode:2010PLoSO...5.9019R. doi:10.1371/journal.pone.0009019. PMC 2814854. PMID 20126400.
19. US 6750221, Garcia-Ladona FJ, Szabo L, Steiner G, Hofmann HP, "Use of 5-HT5-ligands in the treatment of neurodegenerative and neuropsychiatric disturbances", published 2004-06-15
20. Yamazaki M, Okabe M, Yamamoto N, Yarimizu J, Harada K (March 2015). "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. doi:10.1016/j.jphs.2015.02.006. PMID 25837935.
21. Yamazaki M, Harada K, Yamamoto N, Yarimizu J, Okabe M, Shimada T, et al. (October 2014). "ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia". European Neuropsychopharmacology. 24 (10): 1698–1708. doi:10.1016/j.euroneuro.2014.07.009. PMID 25108314.
22. Wu J, Li Q, Bezprozvanny I (October 2008). "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration. 3 (1): 15. doi:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.

Further reading

• Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics. 92 (2–3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.
• Thomas DR (September 2006). "5-ht5A receptors as a therapeutic target". Pharmacology & Therapeutics. 111 (3): 707–714. doi:10.1016/j.pharmthera.2005.12.006. PMID 16516972.
• Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M (December 1994). "Cloning and characterisation of the human 5-HT5A serotonin receptor". FEBS Letters. 355 (3): 242–246. doi:10.1016/0014-5793(94)01209-1. PMID 7988681. S2CID 36425845.
• Schanen NC, Scherer SW, Tsui LC, Francke U (1997). "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. doi:10.1159/000134184. hdl:10722/42533. PMID 8978771.
• The Sanger Centre; The Washington University Genome Sequencing Cente (November 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–1108. doi:10.1101/gr.8.11.1097. PMID 9847074.
• Francken BJ, Josson K, Lijnen P, Jurzak M, Luyten WH, Leysen JE (May 2000). "Human 5-hydroxytryptamine(5A) receptors activate coexpressed G(i) and G(o) proteins in Spodoptera frugiperda 9 cells". Molecular Pharmacology. 57 (5): 1034–1044. PMID 10779389.
• Marazziti D, Ori M, Nardini M, Rossi A, Nardi I, Cassano GB (2001). "mRNA expression of serotonin receptors of type 2C and 5A in human resting lymphocytes". Neuropsychobiology. 43 (3): 123–126. doi:10.1159/000054878. PMID 11287788. S2CID 20724896.
• Iwata N, Ozaki N, Inada T, Goldman D (March 2001). "Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia". Molecular Psychiatry. 6 (2): 217–219. doi:10.1038/sj.mp.4000829. PMID 11317225.
• Grailhe R, Grabtree GW, Hen R (April 2001). "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. doi:10.1016/S0014-2999(01)00933-5. PMID 11343685.
• Noda M, Yasuda S, Okada M, Higashida H, Shimada A, Iwata N, et al. (January 2003). "Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways". Journal of Neurochemistry. 84 (2): 222–232. doi:10.1046/j.1471-4159.2003.01518.x. PMID 12558985. S2CID 7364018.
• Khorana N, Smith C, Herrick-Davis K, Purohit A, Teitler M, Grella B, et al. (August 2003). "Binding of tetrahydrocarboline derivatives at human 5-HT5A receptors". Journal of Medicinal Chemistry. 46 (18): 3930–3937. doi:10.1021/jm030080s. PMID 12930153.
• Dietz BM, Mahady GB, Pauli GF, Farnsworth NR (August 2005). "Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro". Brain Research. Molecular Brain Research. 138 (2): 191–197. doi:10.1016/j.molbrainres.2005.04.009. PMC 5805132. PMID 15921820.

External links

• "5-ht_5a". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Human HTR5A genome location and HTR5A gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.