Disease relevance of 5-HT3R

• Repeated administration of the 5-HT3 receptor antagonist granisetron reduces the incidence of delayed cisplatin-induced emesis in the piglet [1].
• In contrast, the 5-HT3 receptor antagonist, ondansetron (0.3-3 mg/kg i.v.) did not influence the tachycardia induced by 5-HT [2].
• On the other hand, 5-HT3 receptor antagonists ondansetron and granisetron significantly augmented the magnitude of LTP at 1-3 microM and at 0.1-0.3 microM, respectively, without changes in PSA before tetanus [3].
• The fluid accumulation was also measured when Salmonella Typhimurium (10(10) cfu) and CT (20 microg) were instilled for 8 h in ligated loops in jejunum and ileum in pigs given subcutaneous injections of saline or the 5-HT3 receptor antagonist ondansetron (200 microg/kg) [4].

High impact information on 5-HT3R

• One of these is the M-receptor of Gaddum and Picarelli, now called the 5-HT3 receptor, through which 5-HT acts to excite enteric neurons [5].
• Whereas application of acetylcholine activated predominantly a 40-pS channel, 5-HT caused unitary currents apparently through two channels of conductances of 15 and 9 pS, which were reversibly blocked by antagonists of the 5-HT3 receptor [5].
• Potentiation of fast excitatory postsynaptic potentials by cisapride was antagonized by ICS 205-930 (1 microM) but was unaffected by GR 38032F (1 microM), both compounds being 5-HT3-receptor antagonists [6].
• However, the mucosally applied 5-HT3 receptor antagonists ondansetron (5 microM) and granisetron (1 microM) shifted the response curves to mucosally applied 5-HT to the right in a parallel and surmountable manner [7].
• 6. It is concluded that the facilitatory effect of mucosally applied 5-HT to reduce the peristaltic threshold in the guinea pig ileum is mediated via a 5-HT3 receptor located on the mucosal and not the serosal side of the ileum [7].

Biological context of 5-HT3R

• Homology modeling was performed on the N-terminal extracellular regions of human, mouse, and guinea pig 5-hydroxytryptamine type 3A receptors (5-HT3R) based on the 24% sequence homology with and on the crystal structure of the snail acetylcholine binding protein (AChBP) [8].
• Evidence for a 5-HT3 receptor involvement in the facilitation of peristalsis on mucosal application of 5-HT in the guinea pig isolated ileum [7].
• A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog [9].
• The effects of 5-HT3-receptor-related agents on long-term potentiation (LTP) in the mossy fiber-CA3 system were studied in guinea pig hippocampal slices [3].
• All nodose C-fibers responded to transient administration of 5-HT (10 microM) and to the selective 5-HT3 receptor agonist, 2-methyl-5-HT (10 microM), with the action potential discharge [10].

Anatomical context of 5-HT3R

• Distribution and characterisation of the [3H](S)-zacopride labelled 5-HT3 receptor in pig forebrain [11].
• Highest densities of 5-HT3 receptor-associated [3H]-(S)-zacopride binding were detected in areas of porcine spinal cord, nodose ganglion, trigeminal nerve nucleus, area postrema and cerebral cortex, with relatively lower levels in other brain regions (e.g. hippocampus, caudate-putamen) [12].
• We conclude from the present data that the sympathetic nerves of the pig coronary artery are endowed with inhibitory presynaptic 5-HT receptors which do not belong to the 5-HT1, 5-HT2 or 5-HT3 receptor type but seem to represent a so far unknown receptor class [13].
• Serotonin (5-HT) and the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine enhanced electrical field stimulated contractions of the isolated guinea pig trachea [14].
• The selective 5-HT3 receptor antagonist ondansetron (10 microM) inhibited (by approximately 90%) the activation of the nodose C-fibers evoked by 5-HT (10 microM) [10].

Associations of 5-HT3R with chemical compounds

• Curves to 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: a 5-HT3 receptor agonist) and 5-methoxytryptamine (5-MeOT: a 5-HT4 receptor agonist) were monophasic [15].
• By contrast, the potent and selective 5-HT3 receptor antagonist ondansetron (1 microM) was ineffective [16].
• These comparative data with three 5-HT3 receptor antagonists indicate that in animals, zacopride was more potent and longer acting than either ICS 205-930 or GR38032F [17].
• Thus, cisapride acts on the putative 5-HT4 receptor as an agonist and the 5-HT3 receptor as an antagonist [18].
• 3. Solubilized (0.4% Triton X-100) 5-HT3 receptors were affinity purified using Affi-Gel 15 coupled to the high affinity 5-HT3 receptor ligand GR119566X [19].

Regulatory relationships of 5-HT3R

• (2) Both TEA 0.05-0.5 mmol.L-1 and 4-AP 1-10 mumol.L-1 enhanced GPI contractions induced by the selective 5-HT3 receptor agonists 2-methyl-5-HT in concentration-dependent manners [20].

Other interactions of 5-HT3R

• CONCLUSION: The enhancement by TEA and 4-AP of 5-HT3 receptor-mediated GPI contractile responses was due to blocking K+ channels in prejunctional myenteric neurons [20].

Analytical, diagnostic and therapeutic context of 5-HT3R

• Under reducing conditions, SDS-PAGE analysis of the affinity purified 5-HT3 receptor resulted in 3-6 silver stained bands at apparent molecular masses of 37, 44-50, 52, 57-61, 63 and 65-71 kDa (n = 12) [19].
• Unlike protein bands at 45, 50, 60 and 66 kDa, the bands corresponding to proteins of 52, 57, 63 and 71 kDa consistently gave no reaction with an antiserum specific for the cloned A subunit of the 5-HT3 receptor in both a modified dot blot procedure and a Western blot procedure (n = 2-5) [19].
• Using the technique of in vitro receptor autoradiography, we have determined the distribution of the [3H]-(S)-zacopride labelled 5-HT3 receptor in porcine brain [12].

References