As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to
sodium (Na),
potassium (K), and
calcium (Ca) ions. Binding of the
neurotransmitter 5-hydroxytryptamine (
serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitizing, inward current is predominantly carried by
sodium and
potassium ions.[2] 5-HT3 receptors have a negligible permeability to
anions.[1] They are most closely related by homology to the
nicotinic acetylcholine receptor.
Structure
The 5-HT3 receptor differs markedly in structure and mechanism from the other
5-HT receptor subtypes, which are all
G-protein-coupled. A functional channel may be composed of five identical
5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B,[4][5][6][7] 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric).[8] It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor.[9] N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking.[10]
The subunits surround a central
ion channel in a pseudo-symmetric manner (Fig.1). Each subunit comprises an
extracellular N-terminal domain which comprises the orthosteric ligand-binding site; a
transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short
extracellular C-terminus (Fig.1).[1] Whereas extracellular domain is the site of action of
agonists and
competitive antagonists, the
transmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the
cell membrane.[2]
Human and mouse genes
The genes encoding human 5-HT3 receptors are located on
chromosomes 11 (HTR3A, HTR3B) and
3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen from
gene duplications. The genes
HTR3A and
HTR3B encode the 5-HT3A and 5-HT3B subunits and
HTR3C,
HTR3D and
HTR3E encode the 5-HT3C, 5-HT3D and 5-HT3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased
5-HT efficacies. The
pathophysiological role for these additional subunits has yet to be identified.[11]
The human 5-HT3A receptor gene is similar in structure to the mouse gene which has 9
exons and is spread over ~13 kb. Four of its
introns are exactly in the same position as the introns in the homologous
α7-acetylcholine receptor gene, clearly showing their evolutionary relationship.[12][13]
Expression. The 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in the
gut. In human
duodenum and
stomach, for example, 5-HT3C and 5-HT3EmRNA might be greater than for 5-HT3A and 5-HT3B.
Polymorphism. In patients treated with
chemotherapeutic drugs, certain
polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the
5-HTR3B receptor subunit could be used as
biomarker of antiemetic drug efficacy.
Tissue distribution
The 5-HT3 receptor is expressed throughout the
central and
peripheral nervous systems and mediates a variety of physiological functions.[14] On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons,
amygdala, and hippocampus, and in ferret
visual cortex.[15][16][17][18] 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release,[19][20] but evidence is inconclusive.[21]
Effects
When the receptor is activated to open the ion channel by
agonists, the following effects are observed:
Identification of the 5-HT3 receptor did not take place until 1986, lacking selective pharmacological tools.[14] However, with the discovery that the 5-HT3 receptor plays a prominent role in
chemotherapy- and
radiotherapy-induced
vomiting, and the concomitant development of selective
5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry[2][33] and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.[14]
^Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF (1999). "The 5-HT3B subunit is a major determinant of serotonin-receptor function". Nature. 397 (6717): 359–363.
Bibcode:
1999Natur.397..359D.
doi:
10.1038/16941.
PMID9950429.
S2CID4401851.
^Monk SA, Desai K, Brady CA, Williams JM, Lin L, Princivalle A, Hope AG, Barnes NM (2001). "Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus". Neuropharmacology. 41 (8): 1013–1016.
doi:
10.1016/S0028-3908(01)00153-8.
PMID11747906.
S2CID10168401.
^Boyd GW, Low P, Dunlop JI, Ward M, Vardy AW, Lambert JJ, Peters J, Conolly CN (2002). "Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: The role of oligomerisation and chaperone proteins". Mol Cell Neurosci. 21 (1): 38–50.
doi:
10.1006/mcne.2002.1160.
PMID12359150.
S2CID37832903.
^Niesler B, Walstab J, Combrink S, Moeller D, Kapeller J, Rietdorf J, Boenisch H, Goethert M, Rappold G, Bruess M (2007). "Characterization of the Novel Human Serotonin Receptor Subunits 5-HT3C, 5- HT3D and 5-HT3E". Mol Pharmacol. 72 (Mar 28): 8–17.
doi:
10.1124/mol.106.032144.
PMID17392525.
S2CID40072549.
^Niesler, Beate (February 2011). "5-HT3 receptors: potential of individual isoforms for personalised therapy". Current Opinion in Pharmacology. 11 (1): 81–86.
doi:
10.1016/j.coph.2011.01.011.
PMID21345729.
^Quirk, Phillip L.; Rao, Suma; Roth, Bryan L.; Siegel, Ruth E. (2004-08-15). "Three putative N-glycosylation sites within the murine 5-HT3A receptor sequence affect plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells". Journal of Neuroscience Research. 77 (4): 498–506.
doi:
10.1002/jnr.20185.
ISSN0360-4012.
PMID15264219.
S2CID25811139.
^Sanger GJ (September 2008). "5-hydroxytryptamine and the gastrointestinal tract: where next?". Trends in Pharmacological Sciences. 29 (9): 465–471.
doi:
10.1016/j.tips.2008.06.008.
PMID19086255.
^Uetz, P. (1992) Das 5HT3-Rezeptorgen der Maus. Diploma Thesis, University of Heidelberg, 143 pp.
^
abcYakel, JL (2000). Endo, M; Kurachi, Y; Mishina, M (eds.). The 5-HT3 receptor channel: function, activation and regulation in Pharmacology of Ionic Channel Function: Activators and Inhibitors. Handbook of Experimental Pharmacology. Vol. 147. Berlin:
Springer-Verlag. pp. 541–560.
ISBN3-540-66127-1.
^Kazuyoshi Kawa (1994). "Distribution and Functional Properties of 5HT3 Receptors in the Rat Hippocampus Dentate Gyrus". Journal of Neurophysiology. 71 (5): 1935–1947.
doi:
10.1152/jn.1994.71.5.1935.
PMID7520482.
^Imanishi, N.; Iwaoka, K.; Koshio, H.; Nagashima, S. Y.; Kazuta, K. I.; Ohta, M.; Sakamoto, S.; Ito, H.; Akuzawa, S.; Kiso, T.; Tsukamoto, S. I.; Mase, T. (2003). "New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation". Bioorganic & Medicinal Chemistry. 11 (7): 1493–1502.
doi:
10.1016/S0968-0896(02)00557-6.
PMID12628674.
^Delagrange, Philippe; Emerit, M.Boris; Merahi, Nacera; Abraham, Christine; Morain, Philippe; Rault, Sylvain; Renard, Pierre; Pfeiffer, Bruno; Guardiola-Lemaître, Béatrice; Hamon, Michel (1996). "Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization". European Journal of Pharmacology. 316 (2–3): 195–203.
doi:
10.1016/S0014-2999(96)00680-2.
ISSN0014-2999.
PMID8982686.
^Ashoor, A.; Nordman, J.; Veltri, D.; Susan Yang, K. -H.; Shuba, Y.; Al Kury, L.; Sadek, B.; Howarth, F. C.; Shehu, A.; Kabbani, N.; Oz, M. (2013). "Menthol Inhibits 5-Ht3 Receptor-Mediated Currents". Journal of Pharmacology and Experimental Therapeutics. 347 (2): 398–409.
doi:
10.1124/jpet.113.203976.
PMID23965380.
S2CID111928.
^
abcSolt, Ken; Stevens, Renna J.; Davies, Paul A.; Raines, Douglas E. (2005-08-04). "General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition". Journal of Pharmacology and Experimental Therapeutics. 315 (2). American Society for Pharmacology & Experimental Therapeutics (ASPET): 771–776.
doi:
10.1124/jpet.105.090621.
ISSN0022-3565.
PMID16081679.
S2CID22050514.
As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to
sodium (Na),
potassium (K), and
calcium (Ca) ions. Binding of the
neurotransmitter 5-hydroxytryptamine (
serotonin) to the 5-HT3 receptor opens the channel, which, in turn, leads to an excitatory response in neurons. The rapidly activating, desensitizing, inward current is predominantly carried by
sodium and
potassium ions.[2] 5-HT3 receptors have a negligible permeability to
anions.[1] They are most closely related by homology to the
nicotinic acetylcholine receptor.
Structure
The 5-HT3 receptor differs markedly in structure and mechanism from the other
5-HT receptor subtypes, which are all
G-protein-coupled. A functional channel may be composed of five identical
5-HT3A subunits (homopentameric) or a mixture of 5-HT3A and one of the other four 5-HT3B,[4][5][6][7] 5-HT3C, 5-HT3D, or 5-HT3E subunits (heteropentameric).[8] It appears that only the 5-HT3A subunits form functional homopentameric channels. All other subunit subtypes must heteropentamerize with 5-HT3A subunits to form functional channels. Additionally, there has not currently been any pharmacological difference found between the heteromeric 5-HT3AC, 5-HT3AD, 5-HT3AE, and the homomeric 5-HT3A receptor.[9] N-terminal glycosylation of receptor subunits is critical for subunit assembly and plasma membrane trafficking.[10]
The subunits surround a central
ion channel in a pseudo-symmetric manner (Fig.1). Each subunit comprises an
extracellular N-terminal domain which comprises the orthosteric ligand-binding site; a
transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism; a large cytoplasmic domain between M3 and M4 involved in receptor trafficking and regulation; and a short
extracellular C-terminus (Fig.1).[1] Whereas extracellular domain is the site of action of
agonists and
competitive antagonists, the
transmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross the
cell membrane.[2]
Human and mouse genes
The genes encoding human 5-HT3 receptors are located on
chromosomes 11 (HTR3A, HTR3B) and
3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen from
gene duplications. The genes
HTR3A and
HTR3B encode the 5-HT3A and 5-HT3B subunits and
HTR3C,
HTR3D and
HTR3E encode the 5-HT3C, 5-HT3D and 5-HT3E subunits. HTR3C and HTR3E do not seem to form functional homomeric channels, but when co-expressed with HTR3A they form heteromeric complex with decreased or increased
5-HT efficacies. The
pathophysiological role for these additional subunits has yet to be identified.[11]
The human 5-HT3A receptor gene is similar in structure to the mouse gene which has 9
exons and is spread over ~13 kb. Four of its
introns are exactly in the same position as the introns in the homologous
α7-acetylcholine receptor gene, clearly showing their evolutionary relationship.[12][13]
Expression. The 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in the
gut. In human
duodenum and
stomach, for example, 5-HT3C and 5-HT3EmRNA might be greater than for 5-HT3A and 5-HT3B.
Polymorphism. In patients treated with
chemotherapeutic drugs, certain
polymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the
5-HTR3B receptor subunit could be used as
biomarker of antiemetic drug efficacy.
Tissue distribution
The 5-HT3 receptor is expressed throughout the
central and
peripheral nervous systems and mediates a variety of physiological functions.[14] On a cellular level, it has been shown that postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in rat neocortical interneurons,
amygdala, and hippocampus, and in ferret
visual cortex.[15][16][17][18] 5-HT3 receptors are also present on presynaptic nerve terminals. There is some evidence for a role in modulation of neurotransmitter release,[19][20] but evidence is inconclusive.[21]
Effects
When the receptor is activated to open the ion channel by
agonists, the following effects are observed:
Identification of the 5-HT3 receptor did not take place until 1986, lacking selective pharmacological tools.[14] However, with the discovery that the 5-HT3 receptor plays a prominent role in
chemotherapy- and
radiotherapy-induced
vomiting, and the concomitant development of selective
5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry[2][33] and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.[14]
^Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF (1999). "The 5-HT3B subunit is a major determinant of serotonin-receptor function". Nature. 397 (6717): 359–363.
Bibcode:
1999Natur.397..359D.
doi:
10.1038/16941.
PMID9950429.
S2CID4401851.
^Monk SA, Desai K, Brady CA, Williams JM, Lin L, Princivalle A, Hope AG, Barnes NM (2001). "Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus". Neuropharmacology. 41 (8): 1013–1016.
doi:
10.1016/S0028-3908(01)00153-8.
PMID11747906.
S2CID10168401.
^Boyd GW, Low P, Dunlop JI, Ward M, Vardy AW, Lambert JJ, Peters J, Conolly CN (2002). "Assembly and cell surface expression of homomeric and heteromeric 5-HT3 receptors: The role of oligomerisation and chaperone proteins". Mol Cell Neurosci. 21 (1): 38–50.
doi:
10.1006/mcne.2002.1160.
PMID12359150.
S2CID37832903.
^Niesler B, Walstab J, Combrink S, Moeller D, Kapeller J, Rietdorf J, Boenisch H, Goethert M, Rappold G, Bruess M (2007). "Characterization of the Novel Human Serotonin Receptor Subunits 5-HT3C, 5- HT3D and 5-HT3E". Mol Pharmacol. 72 (Mar 28): 8–17.
doi:
10.1124/mol.106.032144.
PMID17392525.
S2CID40072549.
^Niesler, Beate (February 2011). "5-HT3 receptors: potential of individual isoforms for personalised therapy". Current Opinion in Pharmacology. 11 (1): 81–86.
doi:
10.1016/j.coph.2011.01.011.
PMID21345729.
^Quirk, Phillip L.; Rao, Suma; Roth, Bryan L.; Siegel, Ruth E. (2004-08-15). "Three putative N-glycosylation sites within the murine 5-HT3A receptor sequence affect plasma membrane targeting, ligand binding, and calcium influx in heterologous mammalian cells". Journal of Neuroscience Research. 77 (4): 498–506.
doi:
10.1002/jnr.20185.
ISSN0360-4012.
PMID15264219.
S2CID25811139.
^Sanger GJ (September 2008). "5-hydroxytryptamine and the gastrointestinal tract: where next?". Trends in Pharmacological Sciences. 29 (9): 465–471.
doi:
10.1016/j.tips.2008.06.008.
PMID19086255.
^Uetz, P. (1992) Das 5HT3-Rezeptorgen der Maus. Diploma Thesis, University of Heidelberg, 143 pp.
^
abcYakel, JL (2000). Endo, M; Kurachi, Y; Mishina, M (eds.). The 5-HT3 receptor channel: function, activation and regulation in Pharmacology of Ionic Channel Function: Activators and Inhibitors. Handbook of Experimental Pharmacology. Vol. 147. Berlin:
Springer-Verlag. pp. 541–560.
ISBN3-540-66127-1.
^Kazuyoshi Kawa (1994). "Distribution and Functional Properties of 5HT3 Receptors in the Rat Hippocampus Dentate Gyrus". Journal of Neurophysiology. 71 (5): 1935–1947.
doi:
10.1152/jn.1994.71.5.1935.
PMID7520482.
^Imanishi, N.; Iwaoka, K.; Koshio, H.; Nagashima, S. Y.; Kazuta, K. I.; Ohta, M.; Sakamoto, S.; Ito, H.; Akuzawa, S.; Kiso, T.; Tsukamoto, S. I.; Mase, T. (2003). "New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation". Bioorganic & Medicinal Chemistry. 11 (7): 1493–1502.
doi:
10.1016/S0968-0896(02)00557-6.
PMID12628674.
^Delagrange, Philippe; Emerit, M.Boris; Merahi, Nacera; Abraham, Christine; Morain, Philippe; Rault, Sylvain; Renard, Pierre; Pfeiffer, Bruno; Guardiola-Lemaître, Béatrice; Hamon, Michel (1996). "Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization". European Journal of Pharmacology. 316 (2–3): 195–203.
doi:
10.1016/S0014-2999(96)00680-2.
ISSN0014-2999.
PMID8982686.
^Ashoor, A.; Nordman, J.; Veltri, D.; Susan Yang, K. -H.; Shuba, Y.; Al Kury, L.; Sadek, B.; Howarth, F. C.; Shehu, A.; Kabbani, N.; Oz, M. (2013). "Menthol Inhibits 5-Ht3 Receptor-Mediated Currents". Journal of Pharmacology and Experimental Therapeutics. 347 (2): 398–409.
doi:
10.1124/jpet.113.203976.
PMID23965380.
S2CID111928.
^
abcSolt, Ken; Stevens, Renna J.; Davies, Paul A.; Raines, Douglas E. (2005-08-04). "General Anesthetic-Induced Channel Gating Enhancement of 5-Hydroxytryptamine Type 3 Receptors Depends on Receptor Subunit Composition". Journal of Pharmacology and Experimental Therapeutics. 315 (2). American Society for Pharmacology & Experimental Therapeutics (ASPET): 771–776.
doi:
10.1124/jpet.105.090621.
ISSN0022-3565.
PMID16081679.
S2CID22050514.