백서 뇌에서 선택적 세로토닌 재흡수 차단제인 Sertraline이 Serotonin Transporter mRNA의 조절에 미치는 영향

김창윤,김성윤,홍진표,이철,황온유,한오수 大韓神經精神醫學會 1999 신경정신의학 Vol.38 No.5

연구목적 : 항우울제인 sertraline이 전사 수준에서 serotonin transporter의 유전자 발현에 어떤 영향을 주는 지에 대해 상반된 결과가 보고되고 있어 이를 확인하고자 본 연구를 시행하였다. 방 법 : 각 군 당 백서 5마리를 대상으로 처치군에는 sertraline 10mg/kg을, 대조군에는 생리적 식염수를 복강내에 매일 일회 2주간 투여하였다. 마지막 약물 투여 후 24시간 뒤 고정액으로 관류하여 뇌를 적출한 뒤 raphe 부위를 냉동 절삭하여 얻은 절편들에 대해 미리 준비된 ³(???)S-dATP가 부착된 780bp serotonin transporter cDNA probe와 보합결합(in situ hybridization)을 시행하고, 슬라이드에 부착시킨 다음 X-선 필름에 노출시켜 나타난 serotonin transporter mRNA 신호를 image analyzer로 정량 분석하였다. 통계 자료 분석은 대응되는 절편에 대해 paired t-test를 적용하였다. 결 과 : Sertraline 투여 시 serotonin transporter mRNA 농도가 증가하는 경향을 보였다(p<0.05). 결 론 : 이러한 연구 결과는 sertraline 투여에 따라 시냅스 내 serotonin이 증가함에 따라 이를 보상하기 위해 감소시키는 방향으로 serotonin transporter의 유전자 발현이 조절되는 것으로 해석할 수 있다. The knowledge of gene regulation of serotonin transporter mRNA may provide clues to understanding how antidepressants affect their therapeutic actions. Recently, the effects of antidepressants on the serotonin transporter have been investigated but yielded controversial results. To study this further, we performed in situ hybridization for serotonin transporter mRNA in rats(treatment group, n=5)receiving long term(14 days) treatment with a selective serotonin reuptake inhibiting antidepressant, sertraline(10mg/kg, i.p). Following sertraline treatment, a significant(P<0.05)increase in hybridization of serotonin transporter mRNA was observed compared to that observed in vehicle-treated rats(control group, n=5). This result may be interpreted as a compensatory mechanism to reduce synaptic levels of serotonin which were increased by long term sertraline treatment.

항정신병약물로 초래되는 체중 증가와 세로토닌 수송체 유전자 다형성 간의 연관성

최석주(Seok-Ju Choi),하태민(Tae-Min Ha),정치영(Chi-Yong Jung),박세현(Se-Hyeon Park),김영훈(Young-Hoon Kim),공보금(Bo-Geum Kong) 대한생물치료정신의학회 2004 생물치료정신의학 Vol.10 No.2

목적 : 정신분열병 환자의 치료에서 항정신병약물 복용으로 불가피하게 유발되는 체중 증가에 대한 예측 및 위험인자로서 세로토닌수송체 유전적 다형성인 5-HTTPLR이 활용될 수 있는지를 평가하고자 하였다. 방법 : 대상자는 DSM-Ⅳ진단 기준에 부합하고, 최소 12주 이상 대상 항정신병약물 중 한 가지를 단독 복용한 161명의 정신분열병 환자들이었다. 조사 내용은 환자의 성, 연령, 체질량지수, 체중, 약물 종류와 사용기간 등과, 5-HTTLPR(5-HT transporter-linked polymorphic region)의 44 bp insertion/deletion 다형성 분포와 대립 유전자빈도였다. 자료 분석에는 SAS(Ver. 8.1) grogram을 적용하였다. 결과 : 한국인 정신분열병 환자에서 항정신병약물 복용 후 체중 증가는 복용 12주째 2.37㎏ 및 연구시점인 복용 평균 78주째에는 6.92㎏로 조사되었다. 여성, 30세미만, 체질량지수 25미만에서 의미있는 체중 증가가 관찰되었고, 5-HTTLPR이나 대립유전자와는 연관성이 없었다. 결론 : 체중 변화는 성, 연령, 원래의 체질량지수, 항정신병약물의 종류에 따라 다양하게 차이를 보였으며, 항정신병약물 복용으로 유발된 것으로 여겨지는 체중 증가와 5-HTTLPR의 연관성을 규명할 수 없었다. 보다 많은 환자와 교란변수의 엄격한 통제를 통한 보완 연구가 필요하다. Objectives : Using an independent Korean sample, we investigated the association of sex, age, baseline BMI(body mass index) and 44 bp insertion/deletion polymorphism in 5-HTTLPR(5-HT transporter-linked polymorphic region) with antipsychotics-induced weight gain in patients with schizophrenia. Methods : 161 subjects were fulfilling with the DSM-Ⅳ crieteria for schizophrenia. All patients had taken antipsychotics for at least 12 weeks. We reviewed weight changes. We examined the genotype distribution and allele frequency of the serotonin transporter gene 5-HTTLPR in all subjects, using polymerase chain reaction(PCR) of genomic DNA with primers flanking the promotor regions of the 5-HTT gene. Results : There was a significant increase of body weight in those patients whose physical status were female, under 30 years old and under 25 of BMI. Subjects taken atypical antipsychotics were a significant increase of body weight. There was no significant difference in the genotype distribution and allele frequency of 5-HTTLPR between antipsychotics-induced weight gain. Conclusion : There was significant weight gain in female, under 30 years old, under 25 of BMI and taking atypical antipsychotic-medication. These results showed that the genetic polymorphism in 5-HTTLPR is not significantly associated with antipsychotics-induced weight gain in Korean schizophrenic patients.

Association between Serotonin Transporter-Linked Polymorphic Region and Escitalopram Antidepressant Treatment Response in Korean Patients with Major Depressive Disorder

Won, Eun-Soo,Chang, Hun-Soo,Lee, Hwa-Young,Ham, Byung-Joo,Lee, Min-Soo S. Karger 2012 Neuropsychobiology Vol.66 No.4

<P>Abstract</P><P><B><I>Objective:</I></B> Various studies have shown that short (s)/long (l) polymorphisms of the serotonin transporter-linked polymorphic region (5-HTTLPR) might predict treatment outcome to selective serotonin reuptake inhibitors. The purpose of this study was to evaluate the association between 5-HTTLPR and clinical response to escitalopram treatment in Korean subjects with major depressive disorder. <B><I>Methods:</I></B> One hundred and fifteen Korean patients diagnosed with major depressive disorder were evaluated during 8 weeks of escitalopram treatment at a dose of 5–20 mg/day. Patients were genotyped for 5-HTTLPR using polymerase chain reaction. Clinical symptoms were evaluated by the 21-item Hamilton Depression Rating (HAMD-21) scale during the 8 weeks of treatment. <B><I>Results:</I></B> Therapeutic response to antidepressant escitalopram was better in s allele carriers (ss, sl) than in l allele homozygotes (ll) at 8 weeks of treatment (OR = 6.24, p = 0.026). The proportion of s allele carriers in responders was higher than that in non-responders (96.6 vs. 85.7%). The percentile decline in HAMD-21 in s allele carriers (59.86 ± 3.23%) was larger than that in HAMD-21 in l allele homozygotes (43.13 ± 11.49%; p = 0.029). However, 5-HTTLPR genotypes were not significantly associated with remission (p > 0.05). <B><I>Conclusions:</I></B> Our results show that treatment response to escitalopram at 8 weeks was moderated by 5-HTTLPR, with better response rates for s allele carriers than for l allele homozygotes. Although the role of 5-HTTLPR as a definite predictor of selective serotonin reuptake inhibitor treatment response cannot be confirmed from current results, they do suggest a trend for better response in s allele carriers.</P><P>Copyright © 2012 S. Karger AG, Basel</P>

Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder

Lee, Heon-Jeong,Lee, Min-Soo,Kang, Rhee-Hun,Kim, Hyun,Kim, Soon-Duck,Kee, Baik-Seok,Kim, Young Hoon,Kim, Yong-Ku,Kim, Jung Bum,Yeon, Byung Kil,Oh, Kang Seob,Oh, Byung-Hoon,Yoon, Jin-Sang,Lee, Chul,Jun Wiley Subscription Services, Inc., A Wiley Company 2005 Depression and Anxiety Vol.21 No.3

<P>Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. Serotonergic dysfunction has been implicated in PTSD. The present study examined the possible association between the serotonin-transporter-linked polymorphic region (SERTPR) and PTSD. The genotype and allele frequencies of the SERTPR were analyzed in 100 PTSD patients and 197 unrelated healthy controls using a case–control design. The frequency of the s/s genotype was significantly higher in PTSD patients than in normal controls. These findings suggest that the SERTPR s/s genotype is one of the genetic factors for the susceptibility to PTSD. Further investigations are required into the influence of gene polymorphisms on the biological mechanisms of PTSD, its clinical expression, and its response to treatment. Depression and Anxiety 00:1–5, 2005. © 2005 Wiley-Liss, Inc.</P>

도파민과 세로토닌 운반체 및 수용체 영상을 위한 방사선리간드

지대윤(Dae Yoon Chi) 대한핵의학회 2000 핵의학 분자영상 Vol.34 No.3

In the 1980s, techniques to image the human subjects in a rhree-dimensiona1 direction were developed, Two major techniques are SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) which allow the detector to detect a single photon or annihilation photons emitted from the subjects injected with radiopharmaceuticals. Since the latter two techniques can measure the density of receptors, enzymes and transporters in living human, it may be very important project to develop selective methods of labeling with radionuclides and to develop new radiopharmaceuticals. There has been a considerable interest in developing new compounds which specifically bind to dopamine and serotonin receptor and transporters, and it will be thus very useful to label those compounds with radionuclides in order to gain a better understanding in biochemical and pharmacological interactions in living human. This review rnentions the characteristics of radioligands for the imaging of dopamine and serotonin receptors and transporters. Although significant progress has been achieved in the development of new PET and SPECT ligands for in vivo imaging of those receptors and transporters, there are continuous needs of new diagnostic radioligands, (Korean J Nucl Med 2000;34:159-68)

No Association Study of SLC6A4 Polymorphisms with Korean Autism Spectrum Disorder

유희정,조인희,박미라,양소영,김순애,Yoo, Hee Jeong,Cho, In Hee,Park, Mira,Yang, So Young,Kim, Soon Ae The Korean Society of Biological Psychiatry 2009 생물정신의학 Vol.16 No.2

Objectives : The serotonin transporter gene(SLC6A4) is one of the most widely studied candidate genes in autism spectrum disorder(ASD), but there have been conflicting results from studies into the association between SLC6A4 and ASD. The aim of this study was to evaluate the association between single nucleotide polymorphisms(SNPs) in the SLC6A4 gene and ASD in the Korean population. Methods : We selected 12 SNPs in SLC6A4 and observed the genotype of 151 Korean ASD trios. We tested the family-based association for each individual polymorphism and haplotype by using the standard TDT method in Haploview(http://www.broad.mit.edu/mpg/haploview/). Results : Through transmission-disequilibrium testing and haplotype analysis, we could not find any statistically significant transmitted allele or haplotype. In addition, a case-control association test with Korean HapMap data did not reveal any statistical significance. Conclusion : Although serotonin-related genes must be considered candidate genes for ASD, we suggest that common SNPs of SLC6A4 are not important markers for associations with Korean ASD.

Impact of Serotonin Transporter Gene Polymorphism on Gut Motility in Patients With Type 2 Diabetes Mellitus

( Aastha Malik ),( Sarama Saha ),( Rajesh K Morya ),( Sanjay K Bhadada ),( Satya V Rana ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2021 Journal of Neurogastroenterology and Motility (JNM Vol.27 No.2

Background/Aims The pathogenesis of gastrointestinal (GI) symptoms in patients with type 2 diabetes mellitus (T2DM) is yet to be delineated clearly. Serotonin, a monoamine neurotransmitter, resides primarily in the gut and plays a vital role in GI system. However, no study has been documented the role of serotonin and serotonin transporter gene (SLC6A4) polymorphism in the development of GI symptoms in T2DM patients. Methods Three hundred diabetes patients attending diabetes clinic at Postgraduate Institute of Medical Education and Research, Chandigarh, and matched healthy controls were enrolled for this study. Plasma from collected blood sample was used for serotonin measurement by enzyme-linked immunosorbent assay method and buffy coat was used for isolation of DNA by phenol chloroform method. Serotonin transporter gene polymorphism was analyzed by polymerase chain reaction method. Results The frequency of short allele (S) and SS genotype was significantly higher in patients with T2DM than controls and was associated with increased risk of T2DM. The frequency of LS genotype showed an association with protection from the disease. Regarding GI symptoms, 78.2% of patients with constipation showed LL and LS genotypes, and 97.7% of patients with diarrhea had SS genotype. The patients without GI symptoms did not show any association of gut motility with genotype. Furthermore, serotonin was significantly higher in diabetic patients who belonged to SS genotype compared to LS or LL genotype and who presented with diarrhea. Conclusion SS genotypes are prone to develop diarrhea because of faster gut motility resulting from higher serotonin levels as compared to LS and LL genotype in T2DM patients. (J Neurogastroenterol Motil 2021;27:240-247)

한국인 주요 우울장애환자에서 세로토닌 수송체 유전자 다형성

신준호 ( Jun Ho Shin ),백소영 ( So Young Baek ),정상근 ( Sang Keun Chung ),확익근 ( Ik Keun Hwang ) 전북대학교 의과학연구소 2004 全北醫大論文集 Vol.28 No.1

Objectives: There were many studies on serotonin transporter gene(5HTT), one of strong candidate genes related to depression. The results were controversial and even contradictory. The purpose of this study was to examine the relationship of the serotonin transporter gene and Korean major depressive disorder. Methods: The sample consisted of 58 Korean patients with major depressive disorder diagnosed according to DSM-IV criteria and 100 normal controls. They were genotyped at the serotonin transporter gene-linked polymorphic region (5HTTLPR) as s/s, s/1 1/1 genotypes. Results: There were no significant differences in genotypes between two groups(X2=4.490, df=2, p=0.106). There were no significant differences in allele frequency between two groups(X2=0.667, df=1, p=0.414). Conclusion: These results suggest that there is no association between polymorphism of the serotonin transporter gene and Korean major depressive disorder.

Protein Kinase (PKC)-ε Interacts with the Serotonin Transporter (SERT) C-Terminal Region

Il Soo Moon(문일수),Dae-Hyun Seog(석대현) 한국생명과학회 2010 생명과학회지 Vol.20 No.10

Serotonin (5-hydroxytryptamine (5-HT))는 신경계의 세포-세포 간의 신호전달의 주요한 신경전달물질이다. 세포막에 존재하는 serotonin transporter (SERT)는 연접간격에 존재하는 5-HT를 세포 내로 재흡수 하여 세포외부의 5-HT 농도를 조절하지만 그 기전은 아직 밝혀지지 않았다. 본 연구에서는 yeast two-hybrid system을 사용하여 SERT의 C-말단이 protein kinase C-ε (PKC-ε)과 특이적으로 결합함을 알았다. PKC-ε는 PKC의 isotype으로 calcium 비의존적이며 phorbol ester/diacylglycerol 민감성 serine/threonine kinase이다. Na+/Cl- 의존성 SLC6 gene family의 다른 수송체는 PKC-ε과 결합하지 않았다. Deletion mutant들을 사용하여 SERT는 PKC-ε의 C-말단부위와 결합함을 알았으며, 또한 이 단백질간의 결합을 GST pull-down assay로 확인하였다. PKC-ε는 in vitro에서 SERT의 N-말단의 펩티드를 인산화시켰다. 이러한 결과들은 PKC-ε에 의한 SERT의 인산화가 세포막에 존재하는 SERT의 활성을 조절하는 역할을 할 가능성을 시사한다. Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of cell-cell signaling in neuronal systems. The serotonin transporter (SERT) on the plasma membrane controls the extracellular 5-HT level by reuptake of released 5-HT from the synaptic cleft, but the underlying regulation mechanism is unclear. Here, we used the yeast two-hybrid system to identify the specific binding protein(s) that interacts with the carboxyl (C)-terminal region of SERT and found a specific interaction with protein kinase C-ε (PKC-ε), a PKC isotype that is characterized as a calcium-independent and phorbol ester/diacylglycerol-sensitive serine/threonine kinase. PKC-ε bound to the tail region of SERT but not to other members of the Na?/Cl- dependent SLC6 gene family in the yeast two-hybrid assay. The C-terminal region of PKC-ε is essential for interaction with SERT. In addition, these proteins showed specific interactions in the glutathione S-transferase (GST) pull-down assay. PKC-ε phosphorylated the peptide of the SERT amino (N)-terminus in vitro. These results suggest that the phosphorylation of SERT by PKC-ε may regulate SERT activity in plasma membrane.

건강한 성인 및 과민성 장 증후군 환자에서 세로토닌 수송 단백질 유전자의 다형성

이덕용 ( Lee Deog Yong ),박효진 ( Park Hyo Jin ),김원호 ( Kim Won Ho ),이상인 ( Lee Sang In ),서윤주 ( Seo Yun Ju ),최영철 ( Choe Yeong Cheol ) 대한소화기학회 2004 대한소화기학회지 Vol.43 No.1

Background/Aims: Serotonin is thought to be an important neurotransmitter in the pathogenesis of irritable bowel syndrome (IBS). It is reported that functional polymorphism in the promotor region of the serotonin transporter gene is related with the subtypes of IBS and shows racial difference. However, a functional relation between polymorphism and IBS is not clear. The aim of this study was to investigate 5-hydroxytryptamine transporter (5-HTT) gene polymorphism in patients with IBS. Methods: For fifty-six healthy controls and 33 patients with IBS fulfilling Rome II criteria, 5`-flank promotor region of 5-HTT gene was analyzed by polymerase chain reaction. Results: The genotypes of healthy controls were S/S (57.1%), S/L (37.5%), and L/L (5.4%). Those of IBS patients were S/S (54.5%), S/L (36.4%), and L/L (9.1%). IBS patients were divided into three groups: diarrhea predominant (n=15; S/S, 40%; S/L, 53.3%; L/L, 6.7%), constipation predominant (n=12; S/S, 75.0%; S/L, 8.3%; L/L, 16.7%), diarrhea-constipation alternating type (n=6; S/S, 50%; S/L, 50%). There was no statistical difference in the 5-HTT gene polymorphism between patients and controls, and according to the subtypes of IBS patients (p=0.135). Conclusions: There was no relationship between serotonin transporter gene polymorphism and IBS. However, allele S/S genotype was most prominent genotype in both controls and patients. (Korean J Gastroenterol 2004;43:18-22)