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Neurogenic Calcium Signals in Small Arteries

小动脉中的神经源性钙信号

基本信息

批准号：
7172930
负责人：
Withrow Gil Wier
金额：
$ 28.16万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7172930
关键词：
Action Potentials Adrenergic Agents Adrenergic Receptor Affect Arteries Autonomic nervous system Calcitonin Gene-Related Peptide Calcium Signaling Caliber Capsaicin Cholinergic Receptors Chronic Cyclic AMP Data Denervation Development Epinephrine Felis catus Fluo 4 Fluorescence Frequencies GTP-Binding Proteins Goals Image Individual Inositol Isometric Exercise Knock-out Knockout Mice Left Link Measurement Mediating Membrane Potentials Mesentery Microscope Mus Muscle Contraction Nerve Neurotransmitters Numbers Physiological Purinoceptor Rattus Research Resistance Role Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Sensory Sensory Nerve Endings Signal Transduction Site Smooth Muscle Myocytes Testing Time Transgenic Mice Triad Acrylic Resin Varicosity Vasodilation Wild Type Mouse adrenergic afferent nerve neuromuscular transmission neuropeptide Y neurotransmission novel quantum receptor vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The research will focus on the roles and mechanisms of neurogenic Ca 2+ signals in autonomic nervous system control of arterial diameter, particularly the Ca2+ signals generated in smooth muscle cells (SMC) by the concerted action of the sympathetic 'triad' of co-transmitters, ATP, norepinephfine (NE) and neuropeptide Y (NPY). Although components of neurogenic vasoconstriction are attributable to ATP, NE and NPY, the underlying Ca 2+ signals in SMC are not known. Preliminary confocal imaging of Ca 2+ within the SMC of intact pressurized rat mesenteric small arteries during low frequency nerve stimulation has revealed novel Ca2+ transients, putatively associated with excitatory junction potentials (EJPs) and provisionally called "junctional Ca 2+ transients" (jCaTs). With higher frequency stimulation, Ca 2+ 'flashes' (may be due to SMC action potentials) and Ca 2+waves are generated. Stimulation of perivascular sensory nerves elicits vasodilation; preliminary results implicate an increase in the frequency of Ca 2+ sparks. Specific Experimental goals include: 1) Test the hypothesis that jCaTs arise from Ca 2+entering SMCs through P2X1 receptors, which are activated by the ATP contained in one or a few quanta of transmitter, 2) Test the hypothesis that neurally released ATP elicits Ca 2+ influx, but not Ca 2+ waves, 3) Test the hypothesis that neurally released NE elicits Ca 2+ waves that function to activate contraction, 4) Test the hypothesis that neurally released NPY activates the Y1 receptor on SMCS to modulate the effects of NE by changing the frequency of Ca 2+ waves, and 5) Test the hypothesis that calcitonin gene related peptide (CGRP) released from sensory nerves decrease Ca 2+ spark frequency; thus causing vasodilation. Mesenteric small arteries from rats and mice (including a P2Xz-receptor deficient transgenic mouse) will be loaded with fluo-4 and mounted on a confocal myograph for simultaneous Ca2+ imaging, recording of isometric force, and measurement of membrane potential. A real-time confocal microscope will be used to provide 2D images fast enough to resolve jCaTs, flashes and waves. The research will test a comprehensive hypothesis on sympathetic neuromuscular transmission and the control of smooth muscle contraction by the autonomic nervous system: Neurally released ATP activates P2X1 receptors. The resulting Ca 2+ influx activates a small contraction, generates EJPs and is visualized as jCaTs. EJPs may summate to trigger action potentials, visualized as Ca 2+ 'flashes' Neurally released NE and NPY (as metabotropic or G protein-lined receptors) increase the frequency of Ca 2+ waves, which activate strong contraction. By visualizing novel, physiological neurogenic Ca 2+ signals and contraction of intact arteries, the research seeks to provide new information on the concerted action of neurotransmitters in controlling arterial function.

描述(申请人提供)：这项研究将集中于神经源性钙信号在自主神经系统控制动脉直径中的作用和机制，特别是通过交感神经递质三联体、ATP、去甲肾上腺素(NE)和神经肽Y(NPY)的协同作用而在平滑肌细胞(SMC)产生的钙信号。尽管神经源性血管收缩的成分可归因于三磷酸腺苷、去甲肾上腺素和神经肽Y，但SMC中潜在的钙信号尚不清楚。对低频神经刺激时大鼠肠系膜小动脉SMC内钙离子的初步共聚焦成像显示，新的钙瞬变可能与兴奋性连接电位(EjPs)有关，暂时称为“交界性钙瞬变”(JCATS)。在高频刺激下，产生钙闪光(可能是由SMC动作电位引起的)和钙波。刺激血管周围感觉神经可以引起血管扩张；初步结果表明，钙离子火花的频率增加。具体的实验目标包括：1)验证JCAT是由一个或几个递质量子所含的ATP激活的P2X1受体进入SMC内钙的假说；2)验证神经释放的ATP引起钙内流而不是钙波的假说；3)检验神经释放的NE引起钙波激活的假说；4)验证神经释放NPY激活SMC上Y1受体的假说，通过改变钙波的频率来调节NE的作用；5)检验感觉神经释放的降钙素基因相关肽(CGRP)降低钙激发频率的假说；从而导致血管扩张。来自大鼠和小鼠的肠系膜小动脉(包括P2Xz受体缺陷的转基因小鼠)将被负载Flo-4并安装在共聚焦肌图仪上，用于同时进行钙成像、等长力记录和膜电位测量。实时共焦显微镜将被用来提供足够快的2D图像，以解析Jcat、闪光和波。这项研究将检验一个关于交感神经肌肉传递和自主神经系统控制平滑肌收缩的综合假说：神经释放的ATP激活P2X1受体。由此产生的钙离子内流激活了一种小的收缩，产生了EBP，并被可视化为JCATS。ECPs可能通过激活动作电位来触发动作电位，表现为钙离子“闪现”神经释放的NE和NPY(代谢性受体或G蛋白受体)增加钙波的频率，从而激活强烈的收缩。通过可视化新的、生理性的神经源性钙信号和完整动脉的收缩，该研究试图为神经递质在控制动脉功能中的协同作用提供新的信息。