Disease relevance of Htr2c

• 5-HT2C receptor mutant mice consume more food, which leads to late-onset obesity and impaired glucose tolerance [1].
• Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene [2].
• Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite [3].
• Previous studies have shown that mice bearing a targeted disruption of the 5-HT2C receptor gene exhibit an epilepsy syndrome associated with sporadic spontaneous seizures that occasionally result in death [4].
• The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist) [5].

Psychiatry related information on Htr2c

• They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition [6].
• These results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression [7].
• The mismatch between elevated glucocorticoids and maintained 5-HT2C receptor and increased GR gene expression in the hippocampus provides a new model to dissect mechanisms that may underlie affective and eating disorders [8].
• 5-HT2c receptor knock-out mice had more wakefulness, several abnormalities in rapid eye movement sleep expression and an enhanced response to sleep deprivation compared with wild-type control mice [9].
• Compulsive behavior in the 5-HT2C receptor knockout mouse [10].

High impact information on Htr2c

• Sound-induced seizures in serotonin 5-HT2c receptor mutant mice [11].
• Here we show that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration [2].
• To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin [3].
• Introduction of functional 5HT1c receptors into NIH 3T3 cells results, at high frequency, in the generation of transformed foci [12].
• Treatment of mice with fluoxetine alters the pattern of 5-HT2C transcript editing in the direction opposite that observed for suicide victims [13].

Biological context of Htr2c

• Agonist-induced phosphorylation of the serotonin 5-HT2C receptor regulates its interaction with multiple PDZ protein 1 [14].
• Administration of m-chlorophenylpiperazine and fenfluramine, both of which induce anorexic effects via 5-HT2C receptors and/or 5-HT1B receptors, suppressed food intake in 5- and 8-wk-old A(y) mice, whereas the anorexic effects were attenuated in food-restricted A(y) mice [1].
• Restricted feeding significantly decreased hypothalamic 5-HT2C and 5-HT1B receptor gene expression in association with a reversal of the decreases in plasma des-acyl ghrelin levels in 5-wk-old A(y) mice [1].
• RNA editing of the 5-HT2C receptor was exclusively at a single brain-specific site [15].
• The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition [16].

Anatomical context of Htr2c

• In experiments in vitro, isorhynchophylline and isocorynoxeine dose-dependently and competitively inhibited 5-HT-evoked currents in Xenopus oocytes expressing 5-HT2A receptors, but had less of a suppressive effect on those in oocytes expressing 5-HT2C receptors [17].
• The present study used 5-HT2C receptor mutant mice and their wild-type littermates to characterize the 5-HT2 receptor using the 5-HT2 agonists (+/-)-2-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and 1-(3-chlorophenyl)piperazine (mCPP) applied locally in the orbitofrontal cortex (OFC) and head of the caudate nucleus [18].
• Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex [19].
• Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice [19].
• Serotonin increased APPs release 3-4-fold in 3T3 cells stably overexpressing 5-HT2aR or 5-HT2cR [20].

Associations of Htr2c with chemical compounds

• Our present data indicate that the 5-HT2C receptor antagonist RS102221 suppresses MDMA-induced hyperlocomotion [21].
• The electroencephalography defined sleep-waking pattern in rats produced by these two 5-HT2C agonists, as well as fluoxetine, included increased quiet-waking and decreased rapid-eye-movement sleep, which is characteristic of antidepressant drugs [7].
• These results also confirm that 5-HT1B-R activation alone cannot account for the hyperactive response of 5-HT2C KO mice to mCPP [22].
• In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity binding to the serotonin2C (5HT2C) receptors and stimulated turnover of inositol 1,4,5-triphosphate [7].
• However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity [23].

Physical interactions of Htr2c

• In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors [24].
• Estimates of 5-HT2C receptor binding were similar in 5-HT1B KO and WT mice [25].
• The reassociation of the 4-5 S receptor to form the 8 S complex is inhibited by RNase [26].

Regulatory relationships of Htr2c

• In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice [23].
• In contrast, a 4 d treatment with the 5-HT2A/2C agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the C' site and leads to increased expression of 5-HT2C mRNA isoforms encoding receptors that activate G-protein least efficiently [27].

Other interactions of Htr2c

• 5-HT2cR mutant mice develop a late-onset obesity that is associated with higher plasma leptin levels [28].
• Finally, 5-MeO-DIPT had micromolar affinity for 5-HT 2A and 5-HT 2C receptors, but much higher affinity for 5-HT 1A receptors [29].
• The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone [30].
• Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis [4].
• Preincubation of cells with PTX showed that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even to concentrations as low as 20 ng/ml of PTX [31].

Analytical, diagnostic and therapeutic context of Htr2c

• The obtained results suggest that the analgesia induced by m-CPP is mediated by 5-HT2C receptors [32].
• Furthermore, primers specific for the rat 5HT1C receptor sequence did not detect significant levels of receptor mRNA in rat fundus, although the target sequence was amplified a minimum of 10(5)-fold in a polymerase chain reaction [33].
• Here, we briefly describe the techniques of random transgene insertion and gene targeting and discuss how these methods were used to generate the epileptic jerky and 5-hydroxytryptamine (5-HT2C) receptor deficient mice [34].
• Single cell RT-PCR profiling revealed that the vast majority of pyramidal neurons expressed detectable levels of 5-HT2a and/or 5-HT2c receptor mRNA with half of the cells expressing both mRNAs [35].
• To show that the polypeptides detected on western blots and by immunoprecipitation represent the 5-HT2C receptor, binding studies of the 5-HT2C ligand [3H]-mesulergine to immunoprecipitates from extracts of pig choroid plexus were performed [36].

References