Amphetamine Regulation of the Norepinephrine Transporter

安非他明对去甲肾上腺素转运蛋白的调节

• 批准号: 6999134
• 负责人: KEVIN ERREGER
• 金额: $ 4.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999134
• 关键词: amphetamines; binding sites; calcium flux; calmodulin dependent protein kinase; cell line; electrophysiology; enzyme activity; gene mutation; ion transport; kinase inhibitor; membrane channels; membrane transport proteins; neuroregulation; neurotransmitter transport; norepinephrine; phosphorylation; postdoctoral investigator; protein binding; protein kinase C; protein structure function; single cell analysis; syntaxin

DESCRIPTION (provided by applicant): Plasma membrane transporters control the active reuptake of neurotransmitters that mediate chemical signaling in the nervous system. Biogenic amine neurotransmitters (i.e. norepinephrine, NE) play a role in a number of physiological functions including autonomic regulation, locomotion, and complex behaviors such as attention and reward. By terminating these chemical signals, monoamine transporters are critical to the efficient function of the nervous system. The NE system has been implicated in a range of mood and anxiety disorders and the development of drugs such as reboxetine specifically targeting the norepinephrine transporter (NET) are promising therapeutic agents. NET is also a target for drugs of abuse such as the psychostimulants cocaine and amphetamine (AMPH). At present there are few reports of high-resolution measures of intrinsic transporter function. We propose to use NET currents as one measure of transporter activity, including real-time recordings of unitary transporter currents in excised patches. Transporter currents and substrate flux will be used as functional readouts for transporter regulation by AMPH and a range of other modulators. This work will characterize AMPH regulation of monoamine transporter intrinsic function and regulation, and will also be important in building a framework in which to interpret changes caused by physiological modulators, drugs of abuse, and therapeutic agents.

描述（由申请人提供）： 质膜转运蛋白控制神经递质的主动再摄取，从而介导神经系统中的化学信号传导。生物胺神经递质（即去甲肾上腺素，NE）在许多生理功能中发挥作用，包括自主调节、运动和复杂行为（例如注意力和奖励）。通过终止这些化学信号，单胺转运蛋白对于神经系统的有效功能至关重要。 NE 系统与一系列情绪和焦虑障碍有关，专门针对去甲肾上腺素转运蛋白 (NET) 的瑞波西汀等药物的开发是有前途的治疗药物。 NET 也是精神兴奋剂可卡因和安非他明 (AMPH) 等药物滥用的目标。目前关于内在转运蛋白功能的高分辨率测量的报道很少。我们建议使用 NET 电流作为转运蛋白活动的一种测量方法，包括实时记录切除斑块中的单一转运蛋白电流。 转运蛋白电流和底物通量将用作 AMPH 和一系列其他调制器转运蛋白调节的功能读数。这项工作将表征 AMPH 对单胺转运蛋白内在功能和调节的调节，并且对于构建解释生理调节剂、滥用药物和治疗剂引起的变化的框架也很重要。