5-HT3 receptor

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The 5-HT3 receptor belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs) and therefore differs structurally and functionally from all other 5-HT receptors (5-hydroxytryptamine, or serotonin receptors) which are G protein-coupled receptors. [1] [2] [3] This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. [1]

Contents

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]

Figure 1. The subunits are assembled as a pentamer (right) and each subunit has four transmembrane domains (left). Ionophore receptor.jpg
Figure 1. The subunits are assembled as a pentamer (right) and each subunit has four transmembrane domains (left).

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]

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. Structure of the 5HT3 gene in mouse.png
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.

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-HT3E mRNA 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.

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 CDNA structure of the mouse 5HT3 receptor protein.png
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

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:

Agonists

Agonists for the receptor include:

Antagonists

Antagonists for the receptor (sorted by their respective therapeutic application) include:

Positive Allosteric Modulators

These agents are not agonists at the receptor, but increase the affinity or efficacy of the receptors for an agonist:

Discovery

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]

See also

Related Research Articles

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

<span class="mw-page-title-main">Pindolol</span> Chemical compound

Pindolol, sold under the brand name Visken among others, is a nonselective beta blocker which is used in the treatment of hypertension. It is also an antagonist of the serotonin 5-HT1A receptor, preferentially blocking inhibitory 5-HT1A autoreceptors, and has been researched as an add-on therapy to various antidepressants, such as clomipramine and the selective serotonin reuptake inhibitors (SSRIs), in the treatment of depression and obsessive-compulsive disorder.

5-HT<sub>2A</sub> receptor Subtype of serotonin receptor

The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

5-HT<sub>2C</sub> receptor Serotonin receptor protein distributed mainly in the choroid plexus

The 5-HT2C receptor is a subtype of the 5-HT2 receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, it is a G protein-coupled receptor (GPCR) that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located on the X chromosome. As males have one copy of the gene and females have one of the two copies of the gene repressed, polymorphisms at this receptor can affect the two sexes to differing extent.

<span class="mw-page-title-main">HTR3A</span> Protein-coding gene in the species Homo sapiens

5-hydroxytryptamine receptor 3A is a protein that in humans is encoded by the HTR3A gene.

5-HT<sub>4</sub> receptor Protein-coding gene in the species Homo sapiens

5-Hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

5-HT<sub>1B</sub> receptor Mammalian protein found in Homo sapiens

5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.

5-HT<sub>1D</sub> receptor Serotonin receptor which affects locomotion and anxiety in humans

5-hydroxytryptamine (serotonin) receptor 1D, also known as HTR1D, is a 5-HT receptor, but also denotes the human gene encoding it. 5-HT1D acts on the central nervous system, and affects locomotion and anxiety. It also induces vasoconstriction in the brain.

5-HT<sub>1F</sub> receptor Protein-coding gene in the species Homo sapiens

5-hydroxytryptamine (serotonin) receptor 1F, also known as HTR1F is a 5-HT1 receptor protein and also denotes the human gene encoding it.

5-HT<sub>2B</sub> receptor Mammalian protein found in Homo sapiens

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

5-HT<sub>6</sub> receptor Protein-coding gene in the species Homo sapiens

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

5-HT<sub>7</sub> receptor Protein-coding gene in the species Homo sapiens

The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). The 5-HT7 receptor is coupled to Gs (stimulates the production of the intracellular signaling molecule cAMP) and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various blood vessels. This receptor has been a drug development target for the treatment of several clinical disorders. The 5-HT7 receptor is encoded by the HTR7 gene, which in humans is transcribed into 3 different splice variants.

<span class="mw-page-title-main">HTR3B</span> Protein-coding gene in the species Homo sapiens

5-hydroxytryptamine (serotonin) receptor 3B, also known as HTR3B, is a human gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor.

<span class="mw-page-title-main">HTR3C</span> Protein-coding gene in the species Homo sapiens

5-hydroxytryptamine receptor 3C is a protein that in humans is encoded by the HTR3C gene. The protein encoded by this gene is a subunit of the 5-HT3 receptor.

<span class="mw-page-title-main">5-Carboxamidotryptamine</span> Chemical compound

5-Carboxamidotryptamine (5-CT) is a tryptamine derivative closely related to the neurotransmitter serotonin.

<span class="mw-page-title-main">2-Methyl-5-hydroxytryptamine</span> Chemical compound

2-Methyl-5-hydroxytryptamine (2-Methylserotonin, 2-Methyl-5-HT) is a tryptamine derivative closely related to the neurotransmitter serotonin which acts as a moderately selective full agonist at the 5-HT3 receptor.

<span class="mw-page-title-main">SR-57227</span> Chemical compound

SR-57227 is a potent and selective agonist at the 5HT3 receptor, with high selectivity over other serotonin receptor subtypes and good blood–brain barrier penetration.

<span class="mw-page-title-main">25CN-NBOH</span> Chemical compound

25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.

References

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