Role of KCNQ2 Channels in Control of Breathing

KCNQ2 通道在呼吸控制中的作用

基本信息

批准号：
10467261
负责人：
DANIEL K MULKEY
金额：
$ 51.82万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467261
关键词：
Address Affect Animals Binding Brain Breathing Carbon Dioxide Cell Nucleus Chemoreceptors Chronic Coupled Development Electrophysiology (science)Foundations Genes Goals Hydrolysis Hypoventilation Inositol Lead Link Mediating Modeling Mus Mutation Myoclonus Neurodevelopmental Disorder Neurons Neurotransmitters Patients Pharmacology Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Potassium Channel Production Recurrence Regulation Research Respiration Disorders Respiratory Center Role Signal Transduction Slice Symptoms Synapses Syndrome Testing Therapeutic Intervention Tissues Variant Viral Work autism spectrum disorder cofactor epileptic encephalopathies gain of function gain of function mutation genetic manipulation improved knock-down loss of function neonatal brain novel parent grant receptor relating to nervous system respiratory response therapeutic target therapeutically effective

项目摘要

SUMMARY Developmental and epileptic encephalopathy associated with KCNQ2 channels has been primarily linked to loss-of-function KCNQ2 mutations. However, an increasing number of recurrent KCNQ2 gain-of-function variants (i.e., R201C) have been identified. Patients with the KCNQ2R201C mutation display severe myoclonus and early profound hypoventilation due to reduced chemoreflex. Currently, mechanisms by which KCNQ2 channels control the drive to breathe are unclear. The retrotrapezoid nucleus (RTN) is an important respiratory center; neurons in this region function as respiratory chemoreceptors by regulating breathing in response to changes in tissue CO2. Chemosensitive RTN neurons are activated by an increase in CO2/H+, whereas a gain- of-function Kcnq2 mutation might hyperpolarize RTN neurons and make it more difficult to respond to CO2/H+. Indeed, work from the parent grant showed that expression of the recurrent Kcnq2 mutation Kcnq2R201C in RTN neurons blunted the ventilatory response to CO2. Excitingly, we also found that Kcnq2 channel activity in RTN neurons is regulated by a H+-myo-inositol cotransporter (HMIT) which imports myo-inositol to support production of phosphatidylinositol 4,5-bisphosphate (PIP2), an allosteric activator of Kcnq2 channels. HMIT expression in the RTN region is restricted only to chemosensitive neurons. Therefore, we hypothesize that HMIT is required for Kcnq2 channel activity in RTN neurons. In particular, we propose that H+-dependent myo- inositol transport into RTN neurons by HMIT will increase PIP2 levels and activate Kcnq2 channels to limit CO2/H+-stimulated activity, as well as to maintain neural modulation by neurotransmitters that signal through Gq-coupled receptors and PIP2 hydrolysis. Thus, the objective of this application is to determine the extent to which Kcnq2 channels and HMIT interact to control RTN chemoreception under normal conditions and whether HMIT can be targeted to improve breathing in mice that express Kcnq2R201C. The three Specific Aims of this project are: 1) determine the extent to which HMIT influences Kcnq2 channel regulation of chemosensitive RTN neurons; 2) determine contributions of Kcnq2 channels and HMIT interactions to RTN chemoreceptor network excitability; and 3) to establish HMIT in RTN neurons as a therapeutic target for Kcnq2 associated breathing abnormalities. The rationale for this research is that by understanding how HMIT regulates Kcnq2 channel activity in RTN neurons, we can lay a foundation for developing treatments for respiratory problems associated with Kcnq2 mutations.

概括与 KCNQ2 通道相关的发育性和癫痫性脑病主要与 KCNQ2 功能丧失突变。然而，越来越多的复发性 KCNQ2 功能增益变体（即 R201C）已被识别。 KCNQ2R201C 突变患者表现出严重的肌阵挛以及由于化学反射减弱而导致的早期严重通气不足。目前，KCNQ2 的机制控制呼吸驱动力的通道尚不清楚。梯形后核（RTN）是重要的呼吸系统中心;该区域的神经元通过调节呼吸来发挥呼吸化学感受器的作用组织二氧化碳的变化。化学敏感性 RTN 神经元通过 CO2/H+ 的增加而被激活，而增益- 功能丧失的 Kcnq2 突变可能会使 RTN 神经元超极化，使其更难以对 CO2/H+ 做出反应。事实上，来自母体资助的工作表明，RTN 中复发性 Kcnq2 突变 Kcnq2R201C 的表达神经元减弱了对二氧化碳的通气反应。令人兴奋的是，我们还发现 RTN 中的 Kcnq2 通道活动神经元由 H+-肌醇协同转运蛋白 (HMIT) 调节，HMIT 导入肌醇以支持产生磷脂酰肌醇 4,5-二磷酸 (PIP2)，它是 Kcnq2 通道的变构激活剂。汉密尔顿 RTN 区域的表达仅限于化学敏感神经元。因此，我们假设 RTN 神经元中的 Kcnq2 通道活动需要 HMIT。特别是，我们建议 H+ 依赖性肌 HMIT 将肌醇转运至 RTN 神经元将增加 PIP2 水平并激活 Kcnq2 通道以限制 CO2/H+ 刺激的活动，以及通过神经递质维持神经调节，这些神经递质通过 Gq 偶联受体和 PIP2 水解。因此，本申请的目的是确定哪些 Kcnq2 通道和 HMIT 相互作用以控制正常条件下的 RTN 化学感受以及是否 HMIT 可用于改善表达 Kcnq2R201C 的小鼠的呼吸。本次会议的三个具体目标项目有： 1) 确定 HMIT 对化学敏感的 Kcnq2 通道调节的影响程度 RTN神经元； 2) 确定 Kcnq2 通道和 HMIT 相互作用对 RTN 化学感受器的贡献网络兴奋性； 3) 在 RTN 神经元中建立 HMIT 作为 Kcnq2 相关的治疗靶点呼吸异常。这项研究的基本原理是通过了解 HMIT 如何调节 Kcnq2 RTN 神经元的通道活动，我们可以为开发呼吸系统问题的治疗方法奠定基础与 Kcnq2 突变相关。