• Genomics & Informatics
• /
• 제5권2호
• /
• pp.77-82
• /
• 2007

Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol-1,4,5-triphosphate/calcium $(InsP3/Ca^{2+})$ signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and neuromodulin secretion in rat hypothalamic neurons. Specific mRNA transcripts for 5-HT1A, 5-HT2C and 5-HT4 were identified in rat hypothalamic neurons. These experiments were supported by combined techniques such as cAMP and a $Ca^{2+}$ assays in order to elucidate the associated receptors and signaling pathways. The cAMP production and neuromodulin release were profoundly inhibited during the activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor stimulated InsP3 production and caused $Ca^{2+}$ release from the sarcoplasmic reticulum. Selective activation of the Gs-coupled 5-HT4 receptor also stimulated cAMP production, and caused an increase in neuromodulin secretion. These findings demonstrate the ability of 5-HT receptor subtypes expressed in neurons to induce neuromodulin production. This leads to the activation of single or multiple G-proteins which regulate the $InsP3/Ca^{2+}/PLC-{\gamma}$ and adenyl cyclase / cAMP signaling pathways.

• 한국응용곤충학회지
• /
• 제43권2호
• /
• pp.155-162
• /
• 2004

세로토닌 수용체는 세로토닌과 반응하여 세포막의 G단백질을 통해 중개단백질 (adenylyl cyclase, phospholipase C, cGMP phosphodiesterase, ion channel)을 활성화시켜, 이뇨, 기억, 발생 등의 다양한 생리적 반응에 관여한다. 곤충세포인 Schneider2 (S2)와 척추동물 세포인 Chinese hamster ovary (CHO)-Kl에서 Aedes 5-HT$_{7}$ 수용체 유전자 발현을 비교하기 위해, Aedes 5-HT$_{7}$ 수용체 유전자를 형질이입시켰다. 선발된 세포주들(Tr-S2, Tr-CHO)에서 세로토닌 수용체 유전자의 발현은 reverse transcription-PCR, Western blot, immunocytochemistry를 이용하여 확인하였다. 세로토닌 농도증가에 대한 Aedes 5-HT$_{7}$수용체의 기능을 세포 내 cAMP수준을 통해 조사한 결과,Tr-CHO 세포주는 Tr-S2 세포주보다 9배 이상 cAMP수준이 높게 나타났으며, 농도에 의존적이었다. 이 결과는 수용체 유전자가 세포에서 발현되었으나, 세포의 종류와 세포막에 존재하는 G단백질 차이에 따라 중개단백질 활성 차이가 있다는 것을 보여주었다. CHO-Kl 세포에서 Aedes 5-HT$_{7}$ 수용체의 기능이 S2 세포보다 더 효율적이며, Aedes 5-HT$_{7}$ 수용체를 발현하는 Tr-CHO 세포주는 동력제 또는 대립제 검정에 활용될 수 있을 것으로 기대된다. 것으로 기대된다.

• 생물정신의학
• /
• 제5권2호
• /
• pp.215-218
• /
• 1998

The $5-HT_{2A}$ receptor is of great interest for research into schizophrenia and psychopharmacology in light of the observation that schizophrenic patients has 5-HT cortical-subcortical imbalance and atypical antipsychotic clozpine has $5-HT_{2A}$ antagonists properties. An significant association between schizophrenia and the T102C polymorphism of the gene for $5-HT_{2A}$receptor has been reported. In this study, we investigated an association between schizophrenia and the T102C polymorphism of the gene for $5-HT_{2A}$ receptor in Korean schizophrenic patients. The subjects consisted of 139 schizophrenic patients and 88 normal controls. Genomic DNA was amplified by PCR and digested with MsPI. The uncutt product identified allele 1(nucleotide sequence TCT) ; digested products of 216bp and 156bp identified allele 2(nucleotide sequence TCC). The allele frequencies and the genotypic distribution of $5-HT_{2A}$ receptor gene were not significantly different between schizophrenic patients and normal controls. Since allele frequencies of the T102C polymorphism may differ between individuals of different ethnic backgrounds, it needs to be conducted in an advanced research.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1992년도 제1회 신약개발 연구발표회 초록집
• /
• pp.39-39
• /
• 1992

5-Hydroxytryptamine(serotonin, 5-HT)은 중추신경의 신경 전달물질로서 조울병, 불안신경증 등의 정신병태생리에 중요한 역할을 한다. Radioligand 결합실험에 의하여 5-$HT_{1A}$, 5-$HT_{1B}$, 5-$HT_{1C}$, 5-$HT_{1D}$, 5-$HT_{2}$, 5-$HT_3$의 5-HT receptor subtypes의 존재가 확인되어 있고, 그 중에서도 5-$HT_{1A}$ receptor는 중추작용 증 정 도의 조절에 관계가 깊은 raphe nuclei 및 해마에 주로 존재하여 약리학적으로는 체온강하, 혈압 강하, 과식작용, corticosterone 분비 등과 관련되어 있음이 알려져 있다. 따라서 본 수용체 agonist가 항불안약, 항우울약 또는 항고혈압약으로서의 응용이 가능해지면서 5-$HT_{1A}$ 수용체 기능의 해명 및 그 agonist의 개발이 주목받고 있는 가운데, 본 연구에 있어서, 항불안약 개발목적으로 합성된 일련의 화합물 중 1-<3-(3,4-methylene-dioxyphenoxy)propyl> 4-phenyl piperazine (DP-554)이 5-HT 수용체에 특이적이고 선택적으로 높은 친화성을 가지며, rat 해마의 막분획에서 adenylate cyclase 활성을 억제하고, 뇌내 5-HT turnover rate를 감소시키는 둥의 약리학적 작용을 나타내어, 이 화합물이 5-$HT_{1A}$ receptor agonist로서 작용함을 밝혔다. Mouse vas deferens (MVD)를 이용한 실험에서 5-$HT_{1A}$ receptor가 MVD의 교감신경 말단에 존재하여 그 neurotransmission을 억제함이 시사되었으며, 이 조직에서 또한 5-$HT_2$와 5-$HT_3$ 수용체의 존재를 확인하고 각각의 기능을 분명히 했다.

• Biomolecules & Therapeutics
• /
• 제23권5호
• /
• pp.479-485
• /
• 2015

This study was performed to investigate the sedative-hypnotic activity of ${\gamma}$-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the $GABA_A$-benzodiazepine and 5-$HT_{2C}$ receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In $GABA_A$ and 5-$HT_{2C}$ receptor binding assays, FST displayed an effective concentration-dependent binding affinity to $GABA_A$ receptor, similar to the binding affinity to 5-$HT_{2C}$ receptor. FO exhibited higher affinity to 5-$HT_{2C}$ receptor, compared with the $GABA_A$ receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedativehypnotic activity possibly by modulating $GABA_A$ and 5-$HT_{2C}$ receptors. We propose that FST and FO might be effective agents for treatment of insomnia.

• 생물정신의학
• /
• 제11권2호
• /
• pp.146-154
• /
• 2004

Objective:Attention deficit hyperactivity disorder(ADHD) is the most common childhood psychiatric disorder, affecting 3-5% of school-aged children. Although the biological basis of ADHD is unknown, family studies provide strong evidence that ADHD has a genetic basis. Recent genetic studies have suggested associations between ADHD and serotonin 1B(5HT1B) receptor gene G861C polymorphism. The aim of this study is to test for the association between ADHD and 5HT1B receptor gene G861C polymorphism in Korean population. Method:We processed DNA extraction and genotyping. 106 Korean children with ADHD and their parents were analyzed using the transmission disequilibrium test(TDT) and haplotype-based haplotype relative risk (HHRR). And the ADHD children were compared with 212 age and gender matched normal controls. Results:There was no statistical difference of distributions between ADHD cases and controls. We did not observe any preferential transmission of alleles of 5HT1B receptor gene G861C polymorphism in ADHD. Conclusions:Though there is the possibility of failing to detect small genetic effects, our results show no evidence of an association between ADHD and 5HT1B receptor gene G861C polymorphism in the Korean population and indicate that it is unlikely that the 5HT1B receptor is implicated in the susceptibility to ADHD.

• Toxicological Research
• /
• 제12권2호
• /
• pp.171-179
• /
• 1996

To investigate the involvement of $5-HT_{2A}/ 5-HT_{2C} receptors in the developmental toxicity of cocaine in rats, mianserin (2.5 mg/kg), a $5-HT_{2A}/5-HT_{2C}$ receptor antagonist, and/or cocaine HCl (45 mg/kg) were administered intraperitoneally (i.p.), during postnatal days (PND) 7-13. Behavioral assessments for the rat pups were done after 100 days of age by using the progressive ratio schedule of reinforcement (FR 1-FR 128, doubled everyday) and cocaine challenge (5, 15 or 30 mg/kg i.p.) upon established FR 32 behavior. Cocaine injected just prior to the FR 32 session suppressed the established FR 32 responding in a dose-dependent manner. The low dose of cocaine did not affect the FR 32 responding, while the high dose of cocaine suppressed it in all experimental groups. However, by the middle dose of cocaine, rats previously received water-cocaine in their early life showed a marked resistance to cocaine-induced behavioral suppression, and this resistance was not observed in rats received both mianserin and cocaine in their early life. These results suggest that $5-HT_{2A}/ 5-HT_{2C}$ receptors may have an important role for the persistently altered behavioral sensitivity to cocaine caused by exposure to cocaine during development.

• 생물정신의학
• /
• 제10권2호
• /
• pp.133-140
• /
• 2003

Objective:Some candidate gene polymorphisms were reported to be associated with tardive dyskinesia (TD). The aim of this study was to investigate the association of the 5-$HT_{2A}$ receptor gene polymorphisms with TD in Korean schizophrenic subjects. Method:Subjects were of 59 schizophrenic patients with TD and 60 schizophrenic patients without TD for studying of 5-$HT_{2A}$ receptor gene polymorphisms. TD was evaluated using the Abnormal Involuntary Movement Scale(AIMS). Genomic DNA was amplified by PCR and digestion with MspI and BsmI. Result:There were no statistically significant differences in the demographic variables, such as age, male to female percentage, duration of illnesses and duration of antipsychotic drug exposure between the TD group and control group. 1) T102C polymorphisms and TD Comparing the TD group and control group, the 102T/C allele was associated with a significantly increased risk for TD (${\chi}^2$=5.560, df=1, p=0.018). 2) Three AIMS categories of TD and T102C genotype. There were statistically significant differences in the three AIMS categories(${\chi}^2$=6.835, df=2, p=0.033). Conclusion:These result suggest 102T/C genotypes of the 5-$HT_{2A}$ receptor gene are related to the development of TD. The 102T/C genotypes were associated with significantly higher AIMS orofacial dyskinesia scores. These findings suggest that the 5-$HT_{2A}$ receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia.

• 대한한의학회지
• /
• 제26권3호
• /
• pp.239-248
• /
• 2005

Objectives : Electroacupuncture (EA)-induced analgesia has been known to be mediated through the activation of opioid, noradrenergic and serotonergic receptors. However, little study on serotonergic mechanism has been performed in an animal model of chronic pain. The present study was designed to elucidate the type of serotonergic receptors responsible for EA analgesia in the chronic pain model. Methods : In rats with complete Freund's: adjuvant-induced inflammation and spinal nerve injury, spinal wide dynamic range (WDR) cell responses to graded electrical stimulation of afferent C fiber were recorded before and after spinal application of selective 5-hydroxytryptamine (5-HT) receptor antagonists. EA stimulation (2Hz, 0.5msec, 3mA) was applied to the contralateral Zusanli point for 30 min. Results : In both models of chronic pain, WDR cell responses were greatly inhibited after EA stimulation. EA-induced inhibition of WDR celt responses was significantly attenuated by spinal application of non-selective 5-HT receptor antagonist, dihydroergocristine Of 5-HT receptor antagonists tested, 5-HT1A (WAY 100635) and 5-HT2 (LY53857) receptor antagonists strongly reduced an ability of EA stimulation to inhibit WDR cell responses. However, 5-HT1B (GR55562) and 5-HT3 (LY278584) receptor antagonists also had weak but significant blocking action on EA-induced inhibitory effect on chronic pain. Conclusions : Dorsal hem cell responses, afferent C fiber stimulation, chronic pain, electroacupuncture, serotonergic receptors.

• Journal of Ginseng Research
• /
• 제29권1호
• /
• pp.37-43
• /
• 2005

We performed in vitro and in vivo studies to know whether the inhibitory effects of ginsenosides on $5-HT_{3A}$ receptor channel acctivity are coupled to anti-nausea and anti-vomiting action. In vitro study, we investigated the effect of compound K (CK) and M4, which are ginsenoside metabolites, on human $5-HT_{3A}$ receptor channel activity expressed in Xenopus oocytes using two-electrode voltage clamp technique. Treatment of CK or M4 themselves had no effect in both oocytes injected with $H_2O\;and\;5-HT_{3A}$ receptor cRNA. In oocytes injected with $5- HT_{3A}$ receptor cRNA, M4 treatment inhibited more potently 5-HT-induced inward peak current $(I_{5-HT})$ than CK with dose-dependent and reversible manner. The half-inhibitory concentrations $(IC_{50})$ of CK and M4 were $36.9\;\pm\;10.1\;and\;7.3\;\pm\;2.2\;{\mu}M$, respectively. The inhibition of $I_{5-HT}$ by M4 was non-competitive and voltage-independent. These results indicate that M4 might regulate $5-HT_{3A}$ receptors. In vivo experiments, injection of cisplatin (7.5 mg/kg, i.v.) induced both nausea and vomiting with 1 h latency. These episodes reached to peak after 2 h and persisted for 4 h. Pre-treatment of GTS (500 mg/kg, p.o.) significantly reduced cisplatin-induced nausea and vomiting by $51\;\pm\;8.4\;and\;48.8\;\pm\;6.4\%$ during 4 h compared to GIS­untreated group, respectively. These results show the possibility that in vitro inhibition of $5-HT_{3A}$ receptor channel activity by ginsenosides might be coupled to in vivo anti-emetic activity.