Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch K P
Department of Psychiatry, University of Würzburg, Germany.
J Neurochem. 1996 Jun;66(6):2621-4. doi: 10.1046/j.1471-4159.1996.66062621.x.
Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.
情绪、情感、认知和运动功能，以及昼夜节律和神经内分泌节律，包括食物摄入、睡眠和生殖活动，均受中脑缝际5-羟色胺（5-HT）系统调节。通过控制突触后反应的幅度和持续时间，载体介导的5-HT向突触前神经元的转运及其从突触前神经元的释放，对于5-羟色胺能神经传递的精细调节至关重要。环境因素、疾病和治疗引起的5-羟色胺转运体（5-HTT）功能改变及其对早期脑发育、事件相关突触可塑性和神经退行性变的影响机制，受到广泛关注且热度不断增加。我们最近对人和小鼠的5-HTT基因进行了特征分析，并对其5'侧翼调控区进行了功能分析。与人类5-HTT基因转录装置相关的串联重复序列呈现复杂的二级结构，在非5-羟色胺能神经元细胞中抑制启动子活性，并包含正向调控元件。我们现在报告了该重复元件的一种新型多态性，并提供了等位基因依赖性5-HTT启动子活性差异的证据。5-HTT相关功能的等位基因变异可能在复杂性状和行为的表达及调节中发挥作用。
