SIGNAL TRANSDUCTION BY INSULIN-LIKE PEPTIDES IN NEURONS

神经元中胰岛素样肽的信号转导

基本信息

批准号：
2267914
负责人：
JAMES SCHWARTZ
金额：
$ 16.83万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-04-01 至 1996-03-31
项目状态：
已结题

项目摘要

In invertebrates, insulin-like peptides have been convincingly localized to neurons, and some have been shown to fulfill classical criteria expected of neurotransmitters as well as their well-known activities as growth factors and metabolic hormones. Examination of the electrophysiological effects of the mammalian hormone on molluscan neurons reveals that insulin causes hyperpolarization of certain identified neurons of the marine mollusc, Aplysia. cDNA cloning, immunoblot analyses and immunocytochemistry provide evidence for the presence of insulin-like tyrosine kinase receptor(s) in bag cells, neuropil, and in as yet unidentified neurons in central Aplysia ganglia. Immunocytochemistry with both vertebrate and invertebrate anti- insulin antibodies shows staining of neurons, neuropil and gut, indicating the existence of insulin-like Aplysia peptides. Three questions about the presumptive actions of insulin and insulin-like peptides as neurotransmitters that modulate synaptic action will be approached in the nervous system of Aplysia: (1) What is the structure of the endogenous molluscan neuropeptides whose action is mimicked by vertebrate insulin? (2) Are tyrosine kinase signal transduction mechanisms used by these insulin-like peptides to modulate synaptic transmission? and (3) What are the neurophysiological and behavioral effects of insulin-like peptides? The ability of invertebrate neurons to synthesize and release insulins suggests that peptides of the insulin superfamily act not only as hormones to control growth and metabolism, but also as modulatory neurotransmitters. Neuropeptides that function as hormones or growth factors to initiate longer-term metabolic, behavioral or developmental processes also can produce short-term electrophysiological effects on neurons. Specifically, our working hypothesis is that insulin-like peptides serve to integrate behaviors, suppressing activities that are inappropriate when the animal feeds: inking, a defensive behavior, through actions on cell L14, the inking motor neuron, and egg-laying, a reproductive behavior, through actions on the bag cells. The specific experimental advantages Aplysia offer is the opportunity (1) to show that insulin-like peptide(s) act as neuropeptides (as well as hormones); (2) to identify specific neural circuits that mediate or integrate specific behaviors in addition (3) to identify the particular biochemical second messenger pathway(s) and neurophysiological mechanisms within those neurons that underlie the behavior or behavioral changes. To our knowledge, this would be the first opportunity to study a neuropeptide whose actions may be mediated through a tyrosine kinase signal transduction pathway.

在无脊椎动物中，胰岛素样肽已令人信服地定位于神经元，有些人已被证明满足了期望的经典标准神经递质及其知名活动作为增长因素和代谢激素。检查的电生理效应软体动物神经元上的哺乳动物激素揭示了胰岛素的原因海洋软体动物的某些已鉴定神经元的超极化， Aplysia。 cDNA克隆，免疫印迹分析和免疫细胞化学提供证据证明存在胰岛素样酪氨酸激酶受体（S）袋细胞，神经胶体以及中央垂体中尚未确定的神经元神经节。脊椎动物和无脊椎动物抗 - 胰岛素抗体显示神经元，神经肽和肠道的染色，表明存在类似胰岛素的磷脂肽的存在。关于胰岛素和胰岛素样肽的推定作用为调节突触作用的神经递质将在神经的神经系统：（1）内源性的结构是什么软体动物神经肽的作用被脊椎动物胰岛素模仿？（2）是这些使用的酪氨酸激酶信号转导机制胰岛素样肽调节突触传播？（3）什么是胰岛素样肽的神经生理和行为影响？无脊椎动物神经元合成和释放胰岛素的能力表明胰岛素超家族的肽不仅用作激素控制生长和新陈代谢，但也作为调节性神经递质。充当激素或生长因子的神经肽可以启动长期代谢，行为或发展过程也可以对神经元产生短期电生理作用。具体来说，我们的工作假设是胰岛素样肽用于整合行为，抑制动物时不合适的活动提要：墨水，防御行为，通过对细胞L14的作用，通过在袋牢房上的作用。特定的实验优势Aplysia 优惠是机会（1）表明胰岛素样肽（S）起作用神经肽（以及激素）；（2）识别特定神经介导或整合特定行为的电路（3）识别特定的生化第二信使途径和那些神经生理机制，这些神经元的神经元是基于行为或行为改变。据我们所知，这将是第一个研究神经肽的机会，该神经肽的作用可以通过酪氨酸激酶信号转导途径。