Bazalakova M H, Blakely R D
Vanderbilt School of Medicine, Suite 7140, MRB III, Nashville, TN 37232-8548, USA.
Handb Exp Pharmacol. 2006(175):525-44. doi: 10.1007/3-540-29784-7_21.
In cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis. It has previously been shown that HACU is increased by behaviorally and pharmacologically-induced activity of cholinergic neurons in vivo, but the molecular mechanisms of this change in CHT function and regulation have only recently begun to be elucidated. The recent cloning of CHT has led to the generation of new valuable tools, including specific anti-CHT antibodies and a CHT knockout mouse. These new reagents have allowed researchers to investigate the possibility of a presynaptic, CHT-mediated, molecular plasticity mechanism, regulated by and necessary for sustained in vivo cholinergic activity. Studies in various mouse models of cholinergic dysfunction, including acetylcholinesterase (AChE) transgenic and knockout mice, choline acetyltransferase (ChAT) heterozygote mice, muscarinic (mAChR) and nicotinic (mAChR) receptor knockout mice, as well as CHT knockout and heterozygote mice, have revealed new information about the role of CHT expression and regulation in response to long-term alterations in cholinergic neurotransmission. These mouse models highlight the capacity of CHT to provide for functional compensation in states of cholinergic dysfunction. A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia.
在胆碱能神经元中，突触前胆碱转运体（CHT）介导高亲和力胆碱摄取（HACU），这是乙酰胆碱（ACh）合成中的限速步骤。此前已有研究表明，在体内，行为诱导和药物诱导的胆碱能神经元活动可增加HACU，但CHT功能和调节这种变化的分子机制直到最近才开始得到阐明。CHT的近期克隆产生了新的有价值工具，包括特异性抗CHT抗体和CHT基因敲除小鼠。这些新试剂使研究人员能够研究一种由体内持续胆碱能活动调节且对其必要的突触前、CHT介导的分子可塑性机制的可能性。对各种胆碱能功能障碍小鼠模型的研究，包括乙酰胆碱酯酶（AChE）转基因和基因敲除小鼠、胆碱乙酰转移酶（ChAT）杂合子小鼠、毒蕈碱（mAChR）和烟碱（nAChR）受体基因敲除小鼠，以及CHT基因敲除和杂合子小鼠，揭示了关于CHT表达和调节在胆碱能神经传递长期改变中的作用的新信息。这些小鼠模型突出了CHT在胆碱能功能障碍状态下提供功能补偿的能力。更好地理解CHT调节模式应有助于在体内对胆碱能信号进行实验性操纵，这在已知胆碱能功能障碍的人类疾病如阿尔茨海默病、帕金森病、精神分裂症、亨廷顿病和自主神经功能障碍中可能具有潜在应用价值。
