Nomenclature: 5-HT3A

Family: 5-HT3 receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 484 11q23.1 HTR3A 5-hydroxytryptamine (serotonin) receptor 3A, ionotropic 2,8,29
Mouse 4 489 9 A5.3 Htr3a 5-hydroxytryptamine (serotonin) receptor 3A 11,16,18,25
Rat 4 483 8q23 Htr3a 5-hydroxytryptamine (serotonin) receptor 3A, ionotropic 27,29
Previous and Unofficial Names
5-HT3A
5-HT3
HTR3
5-HT3R
5-hydroxytryptamine (serotonin) receptor 3A
5-HT3
5HT3
5-HT-3
5-HT3 receptor
5-HT3-A
5-hydroxytryptamine receptor 3
5-hydroxytryptamine receptor 3A
5HT3 receptor
serotonin receptor 3A
serotonin-gated ion channel receptor
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Functional Characteristics
γ = 0.4-0.8 pS [+ 5-HT3B, γ = 16 pS]; inwardly rectifying current [+ 5-HT3B, rectification reduced]; nH 2-3 [+ 5-HT3B 1-2]; relative permeability to divalent cations reduced by co-expression of the 5-HT3B subunit
Natural/Endogenous Ligands
5-HT
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
palonosetron Hs Antagonist 10.49 pKi 31
pKi 10.49 (Ki 3.2x10-11 M) [31]
vortioxetine Hs Antagonist 8.43 pKi 1
pKi 8.43 (Ki 3.7x10-9 M) [1]
Tissue Distribution
Nucleus tractus solitaris, area postrema, spinal trigeminal nerve nucleus, hippocampus, nucleus accumbens, putamen, caudate.
Species:  Human
Technique:  Autoradiography ([3H]-(S)-zacopride)
References:  33
Hippocampus, caudate nucleus, putamen, nucleus accumbens, amygdala, cervical vagus nerve.
Species:  Human
Technique:  Radioligand Binding ([3H]-granisetron)
References:  9
Area postrema, nucleus tractus solitarius, vagus nerve, striatum, amygdala, olivary nuclei, hippocampus, olfactory bulb, prefrontal cortex.
Species:  Human
Technique:  Radioligand Binding ([3H]GR65630)
References:  24
Pyramidal neurones in the CA2, CA3 and to a lesser extent CA1 fields of the hippocampus. Large neurones in the hilus (CA4) of the hippocampus.
Species:  Human
Technique:  Immunohistochemistry
References:  5
Submucous plexus neurones
Species:  Human
Technique:  Immunohistochemistry
References:  26
Basal epidermal level of the skin.
Species:  Human
Technique:  Immunohistochemistry
References:  23
Piriform, cingulate and entorhinal cortices, hippocampal interneurons, amygdala, olfactory bulb, trochlear nerve nucleus, dorsal tegmental region, facial nerve nucleus, the nucleus of the spinal tract of the trigeminal nerve, spinal cord dorsal horn and dorsal root ganglia.
Species:  Mouse
Technique:  In situ hybridisation
References:  36
Nerve fibres of the urinary bladder.
Species:  Mouse
Technique:  Immunohistochemistry
References:  4
Area postrema, nucleus of the spinal tract of the trigeminal nerve, nucleus solitarius, dorsal motor nucleus of the vagus, cingulate, entorhinal and olfactory cortices, amygdala, lateral dorsal and ventral hippocampus, dentate gyrus, interpenduncular nucleus.
Species:  Rat
Technique:  Radioligand Binding ([125I]DAIZAC))
References:  15
Layers II-III of the neocortex, anterior olfactory nucleus, hippocampal formation, amygdala, trigeminal motor (V) and facial (VII) nuclei, dorsal and the ventral horn of the spinal cord.
Species:  Rat
Technique:  Immunocytochemistry
References:  30
Neurones of the myenteric and submucus plexus, interstitial cells of Cajal.
Species:  Rat
Technique:  Immunohistochemistry
References:  14
Cerebellar cortex.
Species:  Rat
Technique:  Immunohistochemistry
References:  13
Petrosal ganglion.
Species:  Rat
Technique:  Immunohistochemistry
References:  37
Nuclei of the medulla oblongata, spinal cord.
Species:  Rat
Technique:  In situ hybridisation
References:  12
Medial nucleus of the solitary tract.
Species:  Rat
Technique:  Immunocytochemistry
References:  17
Nucleus tractus solitarius, nucleus of the spinal tract of the trigeminal nerve (Sp5), dorsal motor nucleus of the vagal nerve, hippocampus (pyramidal cell layer of CA1 to CA3 and granule cell layer of dentate gyrus), amygdala, frontal, piriform and entorhinal cortices, reticular and paraventricular thalamic nuclei, dorsal horn of the spinal cord.
Species:  Rat
Technique:  Immunohistochemistry
References:  28
Nucleus of the solitary tract, nucleus of the spinal tract of the trigeminal nerve (Sp5), dorsal horn of the spinal cord.
Species:  Rat
Technique:  Immunohistochemistry
References:  10
Tissue Distribution Comments
It is assumed that 5-HT3 receptor selective radioligands reveal the distribution of the 5-HT3A receptor subunit because it is currently viewed as an essential component of the ligand binding site.
Physiological Consequences of Altering Gene Expression
Premature death due to an obstructive urinary retention.
Species:  Mouse
Tissue:  Nervous system, cells of the immune system.
Technique:  Insertion of a gain of function mutant (V290S) of 5-HT3A.
References:  4
Tissue injury-induced persistent, but not acute, nociception is significantly reduced.
Species:  Mouse
Tissue:  Nervous system, cells of the immune system.
Technique:  Absence of 5-HT3A expression (knockout, through gene targeting in embryonic stem cells).
References:  21,38
Decreased adrenocorticotropin responses to restraint or lipopolysaccharide, lower vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus and higher corticotropin-releasing hormone mRNA expression in the central amygdala as compared to wild-type mice.
Species:  Mouse
Tissue:  Nervous system, cells of the immune system.
Technique:  Absence of 5-HT3A expression (knockout through gene targeting in embryonic stem cells).
References:  3
Reduced tail-flick analgesia in response to intrathecal administration of 5-HT.
Species:  Mouse
Tissue:  Nervous system, cells of the immune system.
Technique:  Antisense oligodeoxynucleotide-induced knock-down of 5-HT3A subunit expression.
References:  34
Clinically-Relevant Mutations and Pathophysiology
Disease:  Irritable bowel syndrome (IBS-D)
Role: 
Comments: 
References:  20
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human c.*76G>A 20
Disease:  Bipolar affective disorder (BPAD)
Comments: 
References:  32
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human C178T 32
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  Canonical subunit
Amino acids:  478
Nucleotide accession: 
Protein accession: 
References:  2,29
Type:  Splice variant
Species:  Mouse
Description:  Canonical subunit
Amino acids:  489
Nucleotide accession: 
Protein accession: 
References:  16,25
Type:  Splice variant
Species:  Rat
Description:  A functional splice variant of the rat 5-HT3A subunit thats possesses an additional 5 amino acid residues within the TM3-TM4 linker is differentially regulated during development.
Amino acids:  488
Protein accession: 
References:  27
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The 5HT3A(R334H) polymorphism decreases cell surface expression, but not total abundance, of the receptor.
References:  22
Type:  Splice variant
Species:  Mouse
Description:  A functional splice variant of the mouse 5-HT3A subunit that lacks 6 amino acid residues within the TM3-TM4 linker displays identical single channel conductance to the full length subunit but differs in the efficacy of activation by 2-methyl-5-HT. Agents that activate PKA and PKC differentially modulate the two splice variants.
Amino acids:  483
Nucleotide accession: 
Protein accession: 
References:  11,16,18
Type:  Splice variant
Species:  Rat
Description:  Canonical subunit
Amino acids:  483
Nucleotide accession: 
Protein accession: 
References:  29
Type:  Splice variant
Species:  Human
Description:  An additional splice variant of human 5-HT3A, unofficially named 5-HT3AL, that does not function as a homomeric complex. It's co-assembly with the canonical 5-HT3A subunit is reported to result in receptors that mediate reduced cation flux.
Amino acids:  510
Nucleotide accession: 
Protein accession: 
References:  7-8
Type:  Splice variant
Species:  Human
Description:  An additional splice variant of human 5-HT3A, unofficially named 5-HT3AT, that does not function as a homomeric complex. It's co-assembly with the canonical 5-HT3A subunit is reported to result in receptors that mediate reduced cation flux.
Amino acids:  238
Nucleotide accession: 
Protein accession: 
References:  7-8
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The 5HT3A(A33T) polymorphism reduces maximal response to 5-HT in fluorescence-based membrane potential and Ca2+-imaging assays and also decreases cell surface expression, but not total abundance, of the receptor.
References:  22
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The 5HT3A(C178T) polymorphism, in the regulatory region of the gene, associates with a decrease in amygdaloid activity and influences human face processing, possibly through increased receptor expression.
References:  19
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The 5HT3A(S253N) polymorphism reduces maximal response to 5-HT in fluorescence-based membrane potential and Ca2+-imaging assays.
References:  22
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The 5HT3A(M257I) polymorphism reduces maximal response to 5-HT in fluorescence-based membrane potential and Ca2+-imaging assays and also decreases cell surface expression, but not total abundance, of the receptor.
References:  22
General Comments
5-HT3A subunits function as a homopentameric complex in a variety of recombinant expression systems and display biophysical and pharmacological properties akin to 5-HT3 receptors native to neuroblastoma, neuroblastoma-glioma and neuroblastoma-brain cell hybrid cell lines [2,6,16,25,29,35].

REFERENCES

1. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, Mørk A et al.. (2011) Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J. Med. Chem.54 (9): 3206-21. [PMID:21486038]

2. Belelli D, Balcarek JM, Hope AG, Peters JA, Lambert JJ, Blackburn TP. (1995) Cloning and functional expression of a human 5-hydroxytryptamine type 3AS receptor subunit. Mol. Pharmacol.48 (6): 1054-62. [PMID:8848005]

3. Bhatnagar S, Sun LM, Raber J, Maren S, Julius D, Dallman MF. (2004) Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor. Physiol. Behav.81 (4): 545-55. [PMID:15178147]

4. Bhattacharya A, Dang H, Zhu QM, Schnegelsberg B, Rozengurt N, Cain G, Prantil R, Vorp DA, Guy N, Julius D, Ford AP, Lester HA, Cockayne DA. (2004) Uropathic observations in mice expressing a constitutively active point mutation in the 5-HT3A receptor subunit. J. Neurosci.24 (24): 5537-48. [PMID:15201326]

5. Brady CA, Dover TJ, Massoura AN, Princivalle AP, Hope AG, Barnes NM. (2007) Identification of 5-HT3A and 5-HT3B receptor subunits in human hippocampus. Neuropharmacology52 (5): 1284-90. [PMID:17327132]

6. Brown AM, Hope AG, Lambert JJ, Peters JA. (1998) Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A). J. Physiol. (Lond.)507 ( Pt 3): 653-65. [PMID:9508827]

7. Brüss M, Barann M, Hayer-Zillgen M, Eucker T, Göthert M, Bönisch H. (2000) Modified 5-HT3A receptor function by co-expression of alternatively spliced human 5-HT3A receptor isoforms. Naunyn Schmiedebergs Arch. Pharmacol.362 (4-5): 392-401. [PMID:11111833]

8. Brüss M, Eucker T, Göthert M, Bönisch H. (2000) Exon-intron organization of the human 5-HT3A receptor gene. Neuropharmacology39 (2): 308-15. [PMID:10670426]

9. Bufton KE, Steward LJ, Barber PC, Barnes NM. (1993) Distribution and characterization of the [3H]granisetron-labelled 5-HT3 receptor in the human forebrain. Neuropharmacology32 (12): 1325-31. [PMID:8152523]

10. Doucet E, Miquel MC, Nosjean A, Vergé D, Hamon M, Emerit MB. (2000) Immunolabeling of the rat central nervous system with antibodies partially selective of the short form of the 5-HT3 receptor. Neuroscience95 (3): 881-92. [PMID:10670455]

11. Downie DL, Hope AG, Lambert JJ, Peters JA, Blackburn TP, Jones BJ. (1994) Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes. Neuropharmacology33 (3-4): 473-82. [PMID:7984286]

12. Fonseca MI, Ni YG, Dunning DD, Miledi R. (2001) Distribution of serotonin 2A, 2C and 3 receptor mRNA in spinal cord and medulla oblongata. Brain Res Mol Brain Res89: 11-19. [PMID:11311971]

13. Geurts FJ, De Schutter E, Timmermans JP. (2002) Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum. J. Chem. Neuroanat.24 (1): 65-74. [PMID:12084412]

14. Glatzle J, Sternini C, Robin C, Zittel TT, Wong H, Reeve JR, Raybould HE. (2002) Expression of 5-HT3 receptors in the rat gastrointestinal tract. Gastroenterology123 (1): 217-26. [PMID:12105850]

15. Hewlett WA, Trivedi BL, Zhang ZJ, de Paulis T, Schmidt DE, Lovinger DM, Ansari MS, Ebert MH. (1999) Characterization of (S)-des-4-amino-3-[125I]iodozacopride ([125I]DAIZAC), a selective high-affinity radioligand for 5-hydroxytryptamine3 receptors. J. Pharmacol. Exp. Ther.288 (1): 221-31. [PMID:9862774]

16. Hope AG, Downie DL, Sutherland L, Lambert JJ, Peters JA, Burchell B. (1993) Cloning and functional expression of an apparent splice variant of the murine 5-HT3 receptor A subunit. Eur. J. Pharmacol.245 (2): 187-92. [PMID:7683998]

17. Huang J, Spier AD, Pickel VM. (2004) 5-HT3A receptor subunits in the rat medial nucleus of the solitary tract: subcellular distribution and relation to the serotonin transporter. Brain Res.1028 (2): 156-69. [PMID:15527741]

18. Hubbard PC, Thompson AJ, Lummis SC. (2000) Functional differences between splice variants of the murine 5-HT(3A) receptor: possible role for phosphorylation. Brain Res. Mol. Brain Res.81 (1-2): 101-8. [PMID:11000482]

19. Iidaka T, Ozaki N, Matsumoto A, Nogawa J, Kinoshita Y, Suzuki T, Iwata N, Yamamoto Y, Okada T, Sadato N. (2005) A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. J. Neurosci.25 (27): 6460-6. [PMID:16000636]

20. Kapeller J, Houghton LA, Mönnikes H, Walstab J, Möller D, Bönisch H, Burwinkel B, Autschbach F, Funke B, Lasitschka F, Gassler N, Fischer C, Whorwell PJ, Atkinson W, Fell C, Büchner KJ, Schmidtmann M, van der Voort I, Wisser AS, Berg T, Rappold G, Niesler B. (2008) First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum. Mol. Genet.17 (19): 2967-77. [PMID:18614545]

21. Kayser V, Elfassi IE, Aubel B, Melfort M, Julius D, Gingrich JA, Hamon M, Bourgoin S. (2007) Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. Pain130 (3): 235-48. [PMID:17250964]

22. Krzywkowski K, Jensen AA, Connolly CN, Bräuner-Osborne H. (2007) Naturally occurring variations in the human 5-HT3A gene profoundly impact 5-HT3 receptor function and expression. Pharmacogenet. Genomics17 (4): 255-66. [PMID:17496724]

23. Lundeberg L, El-Nour H, Mohabbati S, Morales M, Azmitia E, Nordlind K. (2002) Expression of serotonin receptors in allergic contact eczematous human skin. Arch. Dermatol. Res.294 (9): 393-8. [PMID:12522576]

24. Marazziti D, Betti L, Giannaccini G, Rossi A, Masala I, Baroni S, Cassano GB, Lucacchini A. (2001) Distribution of [3H]GR65630 binding in human brain postmortem. Neurochem. Res.26 (3): 187-90. [PMID:11495540]

25. Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D. (1991) Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science254 (5030): 432-7. [PMID:1718042]

26. Michel K, Zeller F, Langer R, Nekarda H, Kruger D, Dover TJ, Brady CA, Barnes NM, Schemann M. (2005) Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors. Gastroenterology128 (5): 1317-26. [PMID:15887114]

27. Miquel MC, Emerit MB, Gingrich JA, Nosjean A, Hamon M, el Mestikawy S. (1995) Developmental changes in the differential expression of two serotonin 5-HT3 receptor splice variants in the rat. J. Neurochem.65 (2): 475-83. [PMID:7616200]

28. Miquel MC, Emerit MB, Nosjean A, Simon A, Rumajogee P, Brisorgueil MJ, Doucet E, Hamon M, Vergé D. (2002) Differential subcellular localization of the 5-HT3-As receptor subunit in the rat central nervous system. Eur. J. Neurosci.15 (3): 449-57. [PMID:11876772]

29. Miyake A, Mochizuki S, Takemoto Y, Akuzawa S. (1995) Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. Mol. Pharmacol.48 (3): 407-16. [PMID:7565620]

30. Morales M, Battenberg E, Bloom FE. (1998) Distribution of neurons expressing immunoreactivity for the 5HT3 receptor subtype in the rat brain and spinal cord. J. Comp. Neurol.402 (3): 385-401. [PMID:9853906]

31. Moura Barbosa AJ, De Rienzo F, Ramos MJ, Menziani MC. (2010) Computational analysis of ligand recognition sites of homo- and heteropentameric 5-HT3 receptors. Eur J Med Chem45 (11): 4746-60. [PMID:20724042]

32. Niesler B, Flohr T, Nöthen MM, Fischer C, Rietschel M, Franzek E, Albus M, Propping P, Rappold GA. (2001) Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenetics11 (6): 471-5. [PMID:11505217]

33. Parker RM, Barnes JM, Ge J, Barber PC, Barnes NM. (1996) Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. J. Neurol. Sci.144 (1-2): 119-27. [PMID:8994113]

34. Paul D, Yao D, Zhu P, Minor LD, Garcia MM. (2001) 5-hydroxytryptamine3 (5-HT3) receptors mediate spinal 5-HT antinociception: an antisense approach. J. Pharmacol. Exp. Ther.298 (2): 674-8. [PMID:11454930]

35. Stewart A, Davies PA, Kirkness EF, Safa P, Hales TG. (2003) Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells. Neuropharmacology44 (2): 214-23. [PMID:12623220]

36. Tecott LH, Maricq AV, Julius D. (1993) Nervous system distribution of the serotonin 5-HT3 receptor mRNA. Proc. Natl. Acad. Sci. U.S.A.90 (4): 1430-4. [PMID:8434003]

37. Wang ZY, Keith IM, Olson EB, Vidruk EH, Bisgard GE. (2002) Expression of 5-HT3 receptors in primary sensory neurons of the petrosal ganglion of adult rats. Auton. Neurosci.95 (1-2): 121-4. [PMID:11871776]

38. Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L, Bonhaus DW, Stucky CL, Julius D, Basbaum AI. (2002) The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci.22 (3): 1010-9. [PMID:11826129]

To cite this database page, please use the following:

Nicholas M. Barnes, Tim G. Hales, Sarah C. R. Lummis, Beate Niesler, John A. Peters.
5-HT3 receptors: 5-HT3A. Last modified on 29/05/2014. Accessed on 20/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=373.

Contact us | Print | Back to top | Help
Copyright © 2014 IUPHAR