Identification of serotonin 2A receptor as a novel HCV entry factor by a chemical biology strategy

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HTR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HTR and clinically available 5-HTR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDA-approved 5-HTR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.

Subcellular localization of serotonin 2 A receptor in dorsal hippocampal CA1 area and its effect on neuronal firing / 中国药理学通报

Aim To examine subcellular localization of serotonin 5-HT2A receptor (5-HT2AR) and glutamate NMDA receptor in dorsal hippocampal CA1 area ( dCA1 ) and further explore the effect of systemic acti-vation of 5-HT2A R on hippocampal neuronal firing rate. Methods The distribution of 5-HT2A R and NMDA re-ceptor in the dCA1 region was detected with immune e-lectron microscopy after embedding. The effect of acti-vation of 5-HT2A R on the principal neuron and inter-neuron firing rates was examined with multichannel re-cording. Results 5-HT2A R immunoreactivity was ob-served in the dCA1 neurons, including rough endoplas-mic reticula and mitochondria, and the 5-HT2A R and glutamate NMDA receptors were colocalized in the syn-aptic membrane, vesicle and neurofilament of the hipp-ocampal neuron. 5-HT2A R activation increased princi-pal neuronal firing rate and the interneuronal firing rate was not changed. Conclusion The 5-HT2A R and NM-DA receptor are colocalized in dCA1 neurons, and acti-vation of 5-HT2A R increases hippocampal principal neuronal firing rate.

Effects of Kaixin Jieyu Decoction () on behavior, monoamine neurotransmitter levels, and serotonin receptor subtype expression in the brain of a rat depression model / 中国结合医学杂志

<p><b>OBJECTIVE</b>To determine the mechanisms underlying the anti-depressant effects of Kaixin Jieyu Decoction (, KJD) by investigating the effects of KJD on behavior, monoamine neurotransmitter levels, and serotonin (5-HT) receptor subtype expression in the brain in a rat model of depression.</p><p><b>METHODS</b>The rat depression model was established using chronic unpredictable mild stress (CUMS). Forty-eight Sprague Dawley rats were randomly divided into control, depression model (CUMS), CUMS+KJD (7.7 g/kg(-1)·d(-1) of crude drug), and CUMS+fluoxetine (2.4 mg/kg(-1)·d(-1)) groups (n=12 in each group), and the treatments lasted for 21 days. We regularly evaluated body weight, sucrose consumption, and horizontal and vertical activity scores in open-field tests. The content of the monoamine neurotransmitters 5-HT, norepinephrine (NE), and dopamine (DA) and the DA metabolite homovanillic acid in the cerebral cortex, and 5-HT1A and 5-HT2A receptor mRNA in the cerebral cortex and the hippocampus, were determined respectively by high-performance liquid chromatography-coularray electrochemical detector and real-time polymerase chain reaction.</p><p><b>RESULTS</b>Compared with the control group, CUMS rats showed a variety of depression-like behavioral changes, including a significant reduction in body weight, sucrose consumption, and horizontal and vertical activity scores in open-field tests (P<0.05 or P<0.01), and a significant decrease in 5-HT and NE levels and 5-HT2A receptor mRNA expression. In contrast, they showed a significant increase in 5-HT1A receptor mRNA expression in the cerebral cortex. In the hippocampus, 5-HT1A receptor mRNA expression was lower whereas 5-HT2A receptor mRNA expression was higher than in the control group (P<0.05 or P<0.01). Treatment with KJD or fluoxetine partially attenuated these changes (P<0.05 or P<0.01).</p><p><b>CONCLUSION</b>KJD could normalize the levels of 5-HT and NE and adjust the balance of 5-HT1A and 5-HT2A receptor expression in rat cerebrum, and this may be one of mechanisms of antidepressant effects of KJD.</p>

Association Study of a Serotonin Receptor 2A Gene -1438A/G Polymorphism and Anxiety-Related Traits

OBJECTIVE: The aim of this study was to investigate the relationship between the -1438A/G polymorphism of serotonin receptor 2A (5HTR2A) and anxiety-related traits in Korean adolescent females. METHODS: A total of 174 Korean adolescent females were tested for the -1438A/G polymorphism of 5HTR2A using polymerase chain reaction (PCR)-based methods. Anxiety-related traits were evaluated using the Anxiety Sensitivity Index (ASI) and the trait form of the Spielberg State-Trait Anxiety Inventory (T-STAI). RESULTS: There was no difference between the genotypes with respect to scores pertaining to anxiety-related traits. Although the G allele carriers (GG or AG genotype) scored lower on the psychological subscale of the ASI (4.76+/-3.00 vs 5.98+/-4.00, p=0.038), this difference was not significant after Bonferroni correction. CONCLUSION: These findings suggest that the -1438A/G polymorphism of 5HTR2A might not be associated with anxiety sensitivity or trait anxiety.

Association Analysis of Serotonin 2A Receptor Gene Polymorphism and Obsessive-Compulsive Disorder / 上海第二医科大学学报

0.05). If the patients were divided into two subgroups according to SCID-II, there were significant differences of 5-HT2A genotype between patients without obsessive compulsive personality disorder(OCPD) and controls (P0.05). Conclusion The polymorphism of 5-HT2A receptor gene maybe associated with OCD patients who do not have OCPD in the Han nationality. Patients with or without OCPD may have different etiology.

Association between Suicidal Attempts and Serotonin 2A Receptor Gene Polymorphism T102C in Korean / 대한정신약물학회지

OBJECTIVE: There are several lines of evidence suggested that a serotonergic dysfunction is involved in the susceptibility to suicide. Recently, the T102C polymorphism of the serotonin 2A receptor gene has been suggested to be associated with suicide, but the results of genetic study are still controversial. The purpose of this study was to test whether the T102C polymorphism of the serotonin 2A receptor gene indicates susceptibility to suicidal behavior. METHODS: The genotype and allele frequencies in the T102C polymorphism of the serotonin 2A receptor gene were studied by using TaqMan(R) assay to compare 80 Korean suicidal attempters with 125 Korean healthy controls. RESULTS: The genotype and allele frequencies did not differ between suicidal attempters and control subjects. And, there were no significant associations between the genotypes and violence or non-violence. We also did not find the significant association between the allelic frequencies and violence or non-violence. CONCLUSION: These findings suggest that the T102C polymorphism in serotonin 2A receptor gene is unlikely to play a role in the genetic susceptibility to suicidal behavior, violence or non-violence in Korean suicidal patients.