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素受体细胞表达的多样性如何有助于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赠款＃R01 NS21065的扩展。该项目的中心假设指出，服务于不同效应子模态的神经元表达了烟碱受体亚基的不同组合，作为调节快速兴奋性突触后电位持续时间的一种手段，从而控制了甘吉利昂活性前活性的突触扩增。提出的实验将使用电生理学评估大鼠交感神经和副交感神经元中的烟碱受体。具体目的1是鉴定区分交感神经和副交感神经元功能子集的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整合后果。具体目的2是通过对烟碱受体的α-亚基对α-亚基的系统表征来扩展血管舒缩交感神经元上突触受体的药理特征。目的是为设计新化合物而建立一个合理的基础，这些新化合物对血管舒缩交感神经神经元和其他自主性方式具有很高的选择性。这种化合物可用于进一步剖析不同自主细胞组的作用，并可能具有临床应用。具体目的3是确定α-甲状腺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播。这将测试最近对鸟类自主神经神经节的工作是否在表达α-7烟碱亚基的哺乳动物神经元中也是如此。解决每个特定目标提出的问题将对我们对神经节整合的理解具有根本的影响。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疾病而破坏的自主行为至关重要（例如，心血管适应运动，繁殖，体温调节和防御性适应压力）。