As with other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore. Binding of theneurotransmitter 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 bysodium andpotassium ions.[2] 5-HT3 receptors have a negligible permeability toanions.[1] They are most closely related by homology to thenicotinic acetylcholine receptor.
The 5-HT3 receptor differs markedly in structure and mechanism from the other5-HT receptor subtypes, which are allG-protein-coupled. A functional channel may be composed of five identical5-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]
Figure 1. The subunits are assembled as a pentamer (right) and each subunit has four transmembrane domains (left).
The subunits surround a centralion channel in a pseudo-symmetric manner (Fig.1). Each subunit comprises anextracellular N-terminal domain which comprises the orthosteric ligand-binding site; atransmembrane 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 shortextracellular C-terminus (Fig.1).[1] Whereas extracellular domain is the site of action ofagonists andcompetitive antagonists, thetransmembrane domain contains the central ion pore, receptor gate, and principle selectivity filter that allows ions to cross thecell membrane.[2]
The genes encoding human 5-HT3 receptors are located onchromosomes 11 (HTR3A, HTR3B) and3 (HTR3C, HTR3D, HTR3E), so it appears that they have arisen fromgene duplications. The genesHTR3A andHTR3B encode the 5-HT3A and 5-HT3B subunits andHTR3C,HTR3D andHTR3E 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 increased5-HT efficacies. Thepathophysiological 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 9exons and is spread over ~13 kb. Four of itsintrons are exactly in the same position as the introns in the homologousα7-acetylcholine receptor gene, clearly showing their evolutionary relationship.[12][13]
Figure 2. Structure of the mouse 5HT3 receptor gene, showing its 9 exons (E1-E9), corresponding to the exons shown in the cDNA below. The 5' ends of exons 2, 6, and 9 have alternative splice sites. Figure drawn to scale. Modified after Uetz et al. 1994.[12]
Expression. The 5-HT3C, 5-HT3D and 5-HT3E genes tend to show peripherally restricted pattern of expression, with high levels in thegut. In humanduodenum andstomach, for example, 5-HT3C and 5-HT3EmRNA might be greater than for 5-HT3A and 5-HT3B.
Polymorphism. In patients treated withchemotherapeutic drugs, certainpolymorphism of the HTR3B gene could predict successful antiemetic treatment. This could indicate that the5-HTR3B receptor subunit could be used asbiomarker of antiemetic drug efficacy.
Figure 3. The cDNA sequence of the mouse 5HT3 receptor. The cDNA encodes a 122 nucleotide 5' UTR and a ~510 nucleotide 3' UTR. Boxes indicate exons and the numbers below the exons indicate their length. For instance, the first exon encodes 22 amino acids plus one nucleotide belonging to a split codon with another 2 nucleotides encoded by the next exon. M1-4 indicate the transmembrane helices and C-C indicates the Cysteine loop. Modified after Uetz et al. 1994[12]
The 5-HT3 receptor is expressed throughout thecentral andperipheral 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 ferretvisual 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]
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 inchemotherapy- andradiotherapy-inducedvomiting, and the concomitant development of selective5-HT3 receptor antagonists to suppress these side effects aroused intense interest from the pharmaceutical industry[2][34] and therefore the identification of 5-HT3 receptors in cell lines and native tissues quickly followed.[14]
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^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.
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^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.
^Rondé P, Nichols RA (1997). "5-HT3 receptors induce rises in cytosolic and nuclear calcium in NG108-15 cells via calcium-induced calcium release".Cell Calcium.22 (5):357–365.doi:10.1016/S0143-4160(97)90020-8.PMID9448942.
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