The 5-HT3 Receptor
5-Hydroxytryptamine (5-HT), also known as serotonin, was initially identified as a potent vasoconstrictor present in blood serum (Rapport et al. 1947), but it has become obvious over the years that 5-HT has a multitude of functions, including activation or inhibition of muscle, exocrine and endocrine glands, central and peripheral neurons, and cells of the hematopoietic and immune systems. 5-HT initiates its actions by binding to specific receptor proteins in the cell membrane. These 5-HT receptors were initially subdivided into D and M subtypes, based on their sensitivity to dibenyline or morphine (Gaddum and Picarelli 1957). This was an oversimplification, and currently 5-HT receptors are divided into seven major families (5-HT1–7) based on transduction and structural characteristics. All of these receptors exert their effects via G proteins, except for the 5-HT3 receptor which is a ligand-gated ion channel (LGIC), and, indeed, it is this receptor which is the original M subtype.
The 5-HT3 receptor is a cation-selective member of the Cys-loop family of pentameric ligand-gated ion channels (pLGIC). The receptors are located primarily in the central and peripheral nervous systems, but also present in a wide range of other tissues, including peripheral and sensory ganglia, the gastrointestinal tract, and immune cells such as monocytes, chondrocytes, T-cells, synovial tissue, and platelets, suggesting a physiological importance in many body regions (Barnes et al. 2009; Lummis 2012). The structure of the mouse 5-HT3 receptor has been resolved (Hassaine et al. 2014) and confirms earlier work which showed that this protein is closely related to other pLGIC, including the nACh receptor, the glycine receptor, the GluCl receptor, and the bacterial Cys-loop receptor homologues GLIC and ELIC (see Lummis 2012; Nys et al. 2013; Thompson et al. 2010 for reviews). Activation by 5-HT and other agonists opens an integral cation-selective channel. The receptor is inhibited by a wide range of antagonists, some of which are useful therapeutic agents, and is also modulated by a wide range of substances, including alcohols, steroids, and anesthetics (Barnes et al. 2009; Davies 2011; Lummis 2012; Niesler 2011; Machu 2011).
The transmembrane region contains four membrane-spanning α-helices (M1–M4); M2 from each subunit lines the pore and contains regions responsible for channel gating and ion selectivity. Pore opening results in a rapidly activating and then desensitizing inward current, which is primarily carried by Na+ and K+ ions, although divalent and small organic cations are also permeable. Various compounds are known to block the pore, e.g., picrotoxin, diltiazem, morphine, and quinine. Many of these also act in the pore of other pLGIC, highlighting the common mechanisms that many of these drugs share and also the promiscuity of these compounds. Other modulators, such as alcohols, anesthetics, antidepressants, cannabinoids, opioids, and steroids, may bind in an inter-subunit binding cavity at the top of the transmembrane region, although details are not yet clear.
The long loop between M3 and M4 forms the intracellular domain (ICD); its structure has only been partially resolved, but reveals part of it forms an α-helical region that lines opening (portals) on the intracellular side on the protein (Fig 1). Functionally, the ICD has a role in modulation, interacting with intracellular proteins, confirmation of which has been provided by insertion of this region into a pLGIC that has no intracellular domain that results in modulation by RIC-3 (Goyal et al. 2011). The ICD also contributes to channel conductance: altering charged amino acids that face into the portals alters the conductance. These data explain the large difference in single channel conductance for homomeric 5-HT3A and heteromeric 5-HT3AB receptors; the latter display a much larger conductance (9–17 pS) than the former (sub-pS) due to the presence of three Arg residues in the 5-HT3 A subunit (Kelley et al. 2003; Peters et al. 2010)
5-HT3 receptor antagonists are in use clinically, primarily for controlling chemotherapy and radiotherapy-induced nausea and vomiting and in postoperative nausea and vomiting, but also in a range of gastrointestinal disorders (Machu 2011; Mawe and Hoffman 2013; Niesler 2011). In addition, studies have revealed a diversity of potential disease targets that might be amenable to alleviation by 5-HT3 receptor selective compounds; these include addiction, pruritis, emesis, fibromyalgia, migraine, rheumatic diseases, and neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (Niesler 2011; Thompson and Lummis 2007).)
The 5-HT3 receptor is the only 5-HT receptor that is a ligand-gated ion channel. It is a member of the Cys-loop family of neurotransmitter-gated ion channels, which also includes nACh, glycine, and GABAA receptors. It is a pentamer, and five subunits (A–E) can contribute to a functional receptor, as long as A subunits are present. The large extracellular domain contains the neurotransmitter-binding site which is located between two adjacent subunits. The transmembrane pore is lined by α-helices, and the intracellular domain has a role in channel conductance and receptor modulation. A range of neurological and gastrointestinal diseases may be amenable to treatment with 5-HT3 receptor antagonists, and some compounds are currently in clinical use.
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