Developmental regulation of K+ M-current in brain

大脑 K M 电流的发育调节

• 批准号: 6870689
• 负责人: MELANIE K TALLENT
• 金额: $ 29.55万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-18 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870689
• 关键词: action potentials; confocal scanning microscopy; developmental neurobiology; electrical potential; epilepsy; gene expression; gene mutation; hippocampus; immunocytochemistry; laboratory rat; male; neocortex; neural transmission; neurons; pathologic process; potassium channel; protein localization

DESCRIPTION (provided by applicant): The M-current (IM) is a voltage-dependent K+ current that is important in regulating neuronal excitability. M-channels have slow opening and closing kinetics and do not deactivate. They are partially open in the range of the resting membrane potential and open further upon depolarization. Thus they act as a "clamp" to keep a neuron below its threshold for firing, and profoundly influence the response of a neuron to synaptic input. KCNQ subtypes of K+ channels have been shown to underlie IM; in the brain KCNQ2/KCNQ3 and KCNQ3/KCNQ5 heterotetramers appear to make up native M-channels. Interestingly, mutations in KCNQ subunits have been shown to underlie several human genetic diseases. Mutations in KCNQ2 and KCNQ3 subunits resulting in dysfunctional channels are linked to a congenital epilepsy, benign familial neonatal convulsions (BFNC). This epilepsy is characterized by generalized seizures that appear shortly after birth and spontaneously remit weeks to months later. However a higher incidence of adult epilepsy is seen in these patients. This suggests that IM may be especially critical in immature brain. Our major hypothesis is as follows. In normal human brain a critical level of IM is reached prior to an increase in cortical excitability that appears shortly after birth. This important inhibitory mechanism prevents seizure generation. However, when one of the channels is mutated, as in BFNC, a mismatch appears between expression of appropriate current density and the increase in cortical excitability. This corresponds to the onset of seizures in this disease. Eventually, the "safety threshold" is reached by the mutated channels, but it is developmentally delayed compared to normal channels. Once this safety level is reached, seizures remit. We have designed an integrative approach that it allows us to directly relate developmental changes in subunit expression patterns, IM levels, and IM contribution to both normal and epileptic brain function. The project described in this application should clarify the pathophysiology of this disease and provide insight into the function of IM, that is an important inhibitory regulator in immature brain.

描述（由申请人提供）：M-电流（IM）是一种电压依赖性K+电流，在调节神经元兴奋性方面很重要。M通道具有缓慢的开放和关闭动力学，并且不会失活。它们在静息膜电位范围内部分开放，并在去极化时进一步开放。因此，它们充当“钳”以将神经元保持在其放电阈值以下，并且深刻地影响神经元对突触输入的响应。K+通道的KCNQ亚型已被证明是IM的基础;在大脑中，KCNQ 2/KCNQ 3和KCNQ 3/KCNQ 5异四聚体似乎构成了天然M通道。有趣的是，KCNQ亚基的突变已被证明是几种人类遗传疾病的基础。KCNQ 2和KCNQ 3亚基突变导致通道功能障碍与先天性癫痫、良性家族性新生儿惊厥（BFNC）有关。这种癫痫的特征是出生后不久出现的全身性癫痫发作，并在数周至数月后自发缓解。然而，在这些患者中观察到成人癫痫的发病率较高。这表明IM在未成熟的大脑中可能特别重要。 我们的主要假设如下。在正常人脑中，在出生后不久出现的皮质兴奋性增加之前，IM达到临界水平。这一重要的抑制机制可防止癫痫发作。然而，当其中一个通道发生突变时，如在BFNC中，在适当电流密度的表达和皮质兴奋性的增加之间出现不匹配。这对应于这种疾病的癫痫发作。最终，突变通道达到“安全阈值”，但与正常通道相比，它的发育延迟。一旦达到这一安全水平，癫痫发作就会缓解。我们已经设计了一个综合的方法，它使我们能够直接与亚基表达模式，IM水平，IM的贡献，正常和癫痫脑功能的发展变化。本申请中描述的项目应阐明这种疾病的病理生理学，并提供对IM功能的深入了解，IM是未成熟大脑中的重要抑制调节剂。