Diversity of Nicotinic Synapses in Sympathetic Ganglia

交感神经节烟碱突触的多样性

基本信息

批准号：
6481023
负责人：
JOHN P HORN
金额：
$ 3.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2005-04-30
项目状态：
已结题

项目摘要

The long-term goal of this project is to determine how diversity in the cellular expression of neuronal nicotinic receptors contributes to synaptic function in mammalian sympathetic ganglia. This research will be done in Kiev, Ukraine as an extension of NIH grant #R01 NS21065. The project's central hypothesis states that neurons serving different effector modalities express distinct combinations of nicotinic receptor subunits, as a means for regulating the duration of fast excitatory postsynaptic potentials and thereby controlling the synaptic amplification of preganglionic activity. The proposed experiments will use electrophysiology to assess nicotinic receptors in rat sympathetic and parasympathetic neurons. Specific aim 1 is to identify kinetic features that distinguish nicotinic receptors on functional subsets of sympathetic and parasympathetic neurons. The integrative consequences of these data will then be evaluated using computational models that simulate synaptic activity in autonomic ganglia. Specific aim 2 is to extend the pharmacological profile of synaptic receptors on vasomotor sympathetic neurons by systematic characterization of novel open-channel blockers and antisera against alpha-subunits of nicotinic receptors. The goal is to develop a rational basis for designing new compounds that would be highly selective for vasomotor sympathetic neurons and other autonomic modalities. Such compounds could be used to further dissect the roles of different autonomic cell groups and may have clinical applications. Specific aim 3 is to determine whether alpha-bungarotoxin-sensitive nicotinic receptors contribute to fast synaptic transmission in sympathetic ganglia. This will test whether recent work on avian autonomic ganglia also holds true in mammalian neurons that are known to express the alpha-7 nicotinic subunit. Resolving the issues posed by each specific aim would have fundamental implications for our understanding of ganglionic integration. Nicotinic synapses in autonomic ganglia are important for public health because they are essential for autonomic behaviors that are disrupted by aging and neurological disease (e.g. cardiovascular adaptation to exercise, reproduction, thermoregulation and defensive adaptation to stress).

该项目的长期目标是确定神经元烟碱受体细胞表达的多样性如何促进哺乳动物交感神经节的突触功能。这项研究将在乌克兰基辅进行，作为 NIH 拨款 #R01 NS21065 的延伸。该项目的中心假设指出，服务于不同效应器模式的神经元表达不同的烟碱受体亚基组合，作为调节快速兴奋性突触后电位持续时间的手段，从而控制节前活动的突触放大。拟议的实验将利用电生理学来评估大鼠交感神经元和副交感神经元中的烟碱受体。具体目标 1 是确定区分交感神经元和副交感神经元功能子集上烟碱受体的动力学特征。然后，将使用模拟自主神经节突触活动的计算模型来评估这些数据的综合结果。具体目标2是通过系统表征新型开放通道阻滞剂和针对烟碱受体α亚基的抗血清来扩展血管运动交感神经元上突触受体的药理学特征。目标是为设计对血管运动交感神经元和其他自主神经模式具有高度选择性的新化合物奠定合理的基础。这些化合物可用于进一步剖析不同自主细胞群的作用，并可能具有临床应用。具体目标3是确定α-银环蛇毒素敏感的烟碱受体是否有助于交感神经节中的快速突触传递。这将测试最近对鸟类自主神经节的研究是否也适用于已知表达 α-7 烟碱亚基的哺乳动物神经元。解决每个具体目标所带来的问题将对我们对神经节整合的理解产生根本性的影响。自主神经节中的烟碱突触对公共卫生很重要，因为它们对于因衰老和神经系统疾病而扰乱的自主行为至关重要（例如心血管对运动的适应、生殖、体温调节和对压力的防御适应）。