Gap Junction-Mediated Regulation of Nociceptive Sensory Signaling

间隙连接介导的伤害性感觉信号传导调节

• 批准号: 10049238
• 负责人: Denise Marie Ferkey
• 金额: $ 33.65万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049238
• 关键词: Afferent Neurons; Animal Behavior; Animal Feed; Animal Model; Animals; Aversive Stimulus; Behavior; Behavioral; Binding; Caenorhabditis elegans; Cells; Chemical Synapse; Communication; Complex; Control Animal; Coupling; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dangerousness; Data; Diagnosis; Electrical Synapse; Environment; Environmental Risk Factor; Equilibrium; Esthesia; Excision; Food; Food deprivation (experimental); Foundations; Future; Gap Junctions; Generations; Genetic; Goals; Guanylate Cyclase; Image; Individual; Laboratory Study; Logic; Mediating; Mental disorders; Movement; Nematoda; Nervous System Physiology; Nervous system structure; Neurons; Nociception; Nociceptors; Organism; Oxygen; Personal Satisfaction; Pharmacology; Production; Property; Regulation; Research; Role; Second Messenger Systems; Sensory; Signal Transduction; Site; Stimulus; Synapses; Synaptic Cleft; Testing; Therapeutic; Withdrawal; Work; base; behavioral response; feeding; imaging approach; in vivo imaging; innovation; life history; loss of function; mutant; nervous system disorder; neural circuit; neurotransmitter release; nociceptive response; prevent; relating to nervous system; response; sensory system; vesicular release

Studying the logic of small neural circuits is an essential step toward understanding more complex circuits and, ultimately, the computational and integrative properties of whole nervous systems. With a compact nervous system (just 302 neurons) and a well-characterized behavioral repertoire, the small roundworm C. elegans serves as an excellent animal model to study circuit-level modulation of neuronal function. While chemical synapses allow neurons to communicate with each other through the vesicular release of neurotransmitters into synaptic clefts between the cells, gap junctions allow for direct cytoplasmic communication and electrical coupling between neurons. As such, gap junctions are often referred to as electrical synapses. Importantly, the presence of gap junctions in the nervous system allows for the establishment of even more complex circuits than can be generated by synaptic signaling alone. We have identified a non-cell-autonomous role for guanylyl cyclases in the regulation of nociceptive sensory behaviors, and have gathered evidence for circuit-level modulation of neuronal activity by movement of the second messenger cGMP through gap junctions. As an important step towards our long-term goal of understanding how cellular and intercellular mechanisms interact within neural circuits to control animal behavior, the overall objective of this application is to determine the mechanism by which select guanylyl cyclases modulate nociceptive behavioral responses in C. elegans. Herein we propose to use a combination of genetic, behavioral and neuronal imaging approaches in C. elegans to establish how cGMP generation and movement through gap junctions regulates nervous system function. We will: (1) use in vivo imaging to characterize cGMP and Ca2+ dynamics in a sensory neural circuit, (2) determine the mechanism by which specific guanylyl cyclases modulate ASH nociceptor sensitivity non-cell-autonomously, and (3) define the network(s) of gap junction components that coordinate to pass cGMP to modulate ASH nociceptor sensitivity. Together, these studies will delineate a new means of neuronal communication and a new mechanism for the coordination and optimization of animal behavior. This information is required to develop innovative pharmacological approaches to modulate gap junction signaling for therapeutic goals.

研究小神经回路的逻辑是了解更多的重要一步。 复杂的电路，最终，整个神经系统的计算和整合特性。 有一个紧凑的神经系统（只有302个神经元）和一个特征良好的行为库， 小蛔虫C. elegans是一个很好的动物模型，研究电路水平的调制， 神经元功能虽然化学突触允许神经元通过突触相互交流， 神经递质囊泡释放到细胞之间的突触裂缝，间隙连接允许直接 细胞质通讯和神经元之间的电耦合。因此，缝隙连接通常 称为电突触。重要的是，神经系统中缝隙连接的存在 允许建立比突触信号产生的更复杂的电路 一个人我们已经确定了鸟苷酸环化酶在调节细胞凋亡中的非细胞自主作用。 伤害性感觉行为，并收集了神经元的回路水平调制的证据 第二信使cGMP通过缝隙连接的运动。作为一个重要步骤 我们的长期目标是了解细胞和细胞间机制如何相互作用， 控制动物行为的神经回路，本申请的总体目标是确定 选择鸟苷酸环化酶调节C.优雅的 在这里，我们建议使用遗传，行为和神经成像方法的组合在C。 elegans建立cGMP的产生和运动如何通过间隙连接调节神经 系统功能我们将：（1）使用体内成像来表征感觉系统中cGMP和Ca2+的动力学。 神经回路，（2）确定特定鸟苷酸环化酶调节ASH的机制 伤害感受器敏感性非细胞自主性，和（3）限定间隙连接组件的网络 协调传递cGMP以调节ASH伤害感受器的敏感性。这些研究将 描绘了一种新的神经元通信手段和一种新的协调机制， 优化动物行为。这些信息是开发创新药物所必需的。 调节间隙连接信号传导以达到治疗目的的方法。

项目成果

Methylation of the D2 dopamine receptor affects binding with the human regulatory proteins Par-4 and Calmodulin.

• DOI: 10.17912/micropub.biology.000366
• 发表时间: 2021-02-09
• 期刊: microPublication biology
• 作者: Bowitch A;Sahoo A;Clark AM;Ntangka C;Raut KK;Gollnick P;Yu MC;Pascal SM;Walker SE;Ferkey DM
• 通讯作者: Ferkey DM

The C. elegans OCTR-1 and Human Alpha-2A Adrenergic Receptors are Methylated within the Third Intracellular Loop by Human PRMT5 in vitro.

• DOI: 10.17912/micropub.biology.000546
• 发表时间: 2022
• 期刊: microPublication biology
• 作者: Bowitch, Alexander;Chinsky, Tyler M;Yu, Michael C;Ferkey, Denise M
• 通讯作者: Ferkey, Denise M

INX-18 and INX-19 play distinct roles in electrical synapses that modulate aversive behavior in Caenorhabditis elegans.

INX-18 和 INX-19 在调节秀丽隐杆线虫厌恶行为的电突触中发挥着不同的作用。

• DOI: 10.1371/journal.pgen.1008341
• 发表时间: 2019
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Voelker,Lisa;Upadhyaya,Bishal;Ferkey,DeniseM;Woldemariam,Sarah;L'Etoile,NoelleD;Rabinowitch,Ithai;Bai,Jihong
• 通讯作者: Bai,Jihong

The C. elegans TRPV channel proteins OSM-9 and OCR-2 contribute to aversive chemical sensitivity.

线虫 TRPV 通道蛋白 OSM-9 和 OCR-2 有助于产生厌恶的化学敏感性。

• DOI: 10.17912/micropub.biology.000277
• 发表时间: 2020
• 期刊: microPublication biology
• 作者: Mehle,EmilyA;Sojka,SavannahE;KC,Medha;Zel,RosyM;Reese,SebastianJ;Ferkey,DeniseM
• 通讯作者: Ferkey,DeniseM