NPY Induced Regulation of Sympathetic Neurotransmission

NPY 诱导的交感神经传递调节

• 批准号: 7050619
• 负责人: Thomas C Westfall
• 金额: $ 32.3万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050619
• 关键词: adenosine triphosphate; calcium channel; evoked potentials; laboratory rat; membrane transport proteins; neural transmission; neuropeptide Y; neuropeptide receptor; neuropharmacology; neurotransmitter biosynthesis; neurotransmitter transport; norepinephrine; receptor sensitivity; vascular smooth muscle nervous control; voltage /patch clamp

DESCRIPTION (provided by applicant): Neuropeptide Y (NPY) is known to be co-localized, with norepinephrine (NE) and adenosine triphosphate (ATP) in vascular sympathetic neurons where it is thought to play a role as a co-transmitter/co-modulator. Recent evidence has established that NPYplays a physiological role in sympathetically mediated vasoconstriction by acting on postjunctional Y1 receptors. NPY is also known to exert prejunctional effects leading to inhibition of NE and most likely ATP release and an increase in NPY-ir release via Y2 receptors as well as inhibition of NE synthesis via Y3 and Y5 receptors. These results suggest that the process of NE synthesis and release of sympathetic co-transmitters may be differentially modulated by NPY suggesting an additional level of control in the prejunctional regulation of sympathetic neurotransmission. However the physiological role of this action has not been completely established. We have obtained evidence that an important mechanism for the prejunctional effects of NPY is through inhibition of Ca 2+channels. There is also evidence for a role of SNARE proteins in the preferential release and modulation of transmitter releaseby auto and heteroreceptors. The purpose of the present proposal is to further investigate the physiological role (Aims 1 and 2) on the NPY induced modulation of sympathetic co-transmitter release and NE release and the mechanisms involved (Aim 3) in the prejunctional modulation by NPY and other mediators. The rationale for studies proposed in Aim 1 is as follows: If there is endogenous modulation of transmitter release by NPY, then agonists and antagonists specific for the prejunctional NPY autoreceptor should alter evoked transmitter release in a manner consistent with the receptors being activated by endogenous agonist (e.g. released NPY). In other words, the effect of exogenously administered agonists and antagonists should vary with the biophase concentration of endogenous NPY. The response of the effector cell should be consistent with inhibition or stimulation ofNPY release. It would also seem necessary to demonstrate functional receptors in vivo. A similar rationale exists for Aim 2. In Aim 1 we examine the effect of a series of selective Y1 and Y2 agonists and antagonists on the nerve stimulation evoked release of NE, NPY-ir and ATP as well as perfusion pressure in the mesenteric arterial bed. This will be done before and after the endogenous NPY concentration is elevated by: 1) increasing the frequency of nerve stimulation or 2) decreasing the perfusion rate; or 3) after the NPY concentration has been reduced by depletion of tissue levels acutely or chronically. We will also examine the in vivo effect of agonists and antagonists in the pithed rat preparation. In Aim 2 similar experiments will evaluate the effect of NPY drugs on the nerve stimulation evoked increase in NE synthesis as measured by DOPA accumulations after decarboxylase inhibition. In Aim 3 we will determine if interruption of SNARE proteins by Botulinum neurotoxins (BoNTs) inhibit the evoked release of NE, NPY-ir and ATP as a mechanism for preferential release or differentiated modulation. We will also examine if signaling through SNARE proteins contributes to the prejunctional modulation by NPY. These studies will provide useful new information on the functional role and mechanism of action of NPY in the prejunctional regulation of sympathetic neurotransmission.

描述（由申请人提供）：已知神经肽Y（NPY）与去甲肾上腺素（NE）和三磷酸腺苷（ATP）共定位于血管交感神经元中，在血管交感神经元中，神经肽Y被认为起共递质/共调节剂的作用。最近的证据表明，NPY通过作用于连接后Y1受体在交感神经介导的血管收缩中发挥生理作用。还已知NPY发挥连接前作用，导致NE和最可能的ATP释放的抑制和经由Y2受体的NPY-ir释放的增加以及经由Y3和Y 5受体的NE合成的抑制。这些结果表明，NE的合成和释放的交感神经共递质的过程中，可能会受到不同的调制，这表明在交感神经传递的连接前调节的控制水平的NPY。然而，这种作用的生理作用尚未完全确定。我们发现NPY的连接前效应的一个重要机制是通过抑制Ca 2+通道。也有证据表明SNARE蛋白在优先释放和调节自身和异源受体释放递质中的作用。本建议的目的是进一步研究NPY诱导的交感神经共递质释放和NE释放的调节的生理作用（目的1和2）以及NPY和其他介质的连接前调节中涉及的机制（目的3）。目标1中提出的研究的基本原理如下：如果存在NPY对递质释放的内源性调节，则对连接前NPY自身受体特异性的激动剂和拮抗剂应以与受体被内源性激动剂激活（例如释放的NPY）一致的方式改变诱发的递质释放。换句话说，外源性给药的激动剂和拮抗剂的作用应随内源性NPY的生物相浓度而变化。效应细胞的反应应与抑制或刺激NPY释放一致。似乎也有必要在体内证明功能性受体。目标2也有类似的理由。在目的1中，我们研究了一系列选择性Y1和Y2激动剂和拮抗剂对神经刺激诱发的NE，NPY-ir和ATP释放以及肠系膜动脉床灌注压的影响。这将在内源性NPY浓度升高之前和之后通过以下方式进行：1）增加神经刺激的频率或2）降低灌注速率;或3）在NPY浓度已经通过急性或慢性消耗组织水平而降低之后。我们还将检查激动剂和拮抗剂在去髓大鼠制剂中的体内作用。在目的2中，类似的实验将评估NPY药物对神经刺激诱发的NE合成增加的作用，如通过脱羧酶抑制后的多巴积累所测量的。在目的3中，我们将确定是否通过肉毒神经毒素（BoNT）中断SNARE蛋白抑制NE、NPY-ir和ATP的诱发释放作为优先释放或分化调节的机制。我们还将研究通过SNARE蛋白的信号传导是否有助于NPY的连接前调节。这些研究将为神经肽Y在交感神经传递的连接前调节中的功能作用和作用机制提供有用的新信息。

项目成果

Endothelin-induced modulation of neuropeptide Y and norepinephrine release from the rat mesenteric bed.

内皮素诱导的神经肽 Y 和去甲肾上腺素从大鼠肠系膜床释放的调节。

• DOI: 10.1152/ajpheart.00177.2001
• 发表时间: 2002
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Hoang,Dan;Macarthur,Heather;Gardner,Alice;Westfall,ThomasC
• 通讯作者: Westfall,ThomasC

Influence of cold stress on neuropeptide Y and sympathetic neurotransmission.

冷应激对神经肽Y和交感神经传递的影响。

• DOI: 10.1016/j.peptides.2005.05.024
• 发表时间: 2005
• 期刊: Peptides
• 影响因子: 3
• 作者: Han,Songping;Chen,Xiaoli;Yang,Chun-Lian;Vickery,Lillian;Wu,Yumei;Naes,Linda;Macarthur,Heather;Westfall,ThomasC
• 通讯作者: Westfall,ThomasC

Interactions of neuropeptide y, catecholamines, and angiotensin at the vascular neuroeffector junction.

• DOI: 10.1016/b978-0-12-411512-5.00006-3
• 发表时间: 2013
• 期刊: Advances in pharmacology
• 作者: T. Westfall;H. Macarthur;M. Byku;Chun-lian Yang;J. Murray

Endothelin (ET)-1-induced inhibition of ATP release from PC-12 cells is mediated by the ETB receptor: differential response to ET-1 on ATP, neuropeptide Y, and dopamine levels.

内皮素 (ET)-1 诱导的 PC-12 细胞 ATP 释放抑制是由 ETB 受体介导的：ET-1 对 ATP、神经肽 Y 和多巴胺水平的不同反应。

• DOI: 10.1124/jpet.104.081075
• 发表时间: 2005
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Gardner,A;Westfall,TC;Macarthur,H
• 通讯作者: Macarthur,H

Neuropeptide Y and sympathetic control of vascular tone in hypertension.

神经肽 Y 和交感神经对高血压血管张力的控制。

• DOI: 10.1007/3-7643-7417-9_6
• 发表时间: 2006
• 期刊: EXS.
• 作者: Westfall,ThomasC