Calcium-permeable AMPA receptors and their auxiliary subunits: pharmacological and molecular intervention in health and disease

钙渗透性 AMPA 受体及其辅助亚基：健康和疾病的药理学和分子干预

• 批准号: MR/T002506/1
• 负责人: Mark Farrant
• 金额: $ 264.27万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT002506%2F1
• 关键词: Calcium; permeable; AMPA; receptors; their

All of our sensations, thoughts, movements, emotions, and memories are produced by the electrical activity of neurons in our nervous system. The transfer of information between these cells relies on the release of a chemical signal at specialised points of contact - synapses. In the mammalian brain glutamate is the main excitatory transmitter, released from one neuron to activate glutamate receptors embedded in the postsynaptic membrane of neighbouring cells. By this means, electrical nerve impulses are transmitted between neurons.While several different types of glutamate receptor exist within the brain, signalling by one family - the AMPA receptors (AMPARs) - is central to virtually all brain functions, being responsible for most fast signalling, and longer-term processes intimately associated with changes in the function of synapses and circuits. One of the defining features of the healthy brain is its ability to retain information arising from experience. Changes in AMPAR properties are important in the laying down of such memories. This process involves alterations in the number or efficiency of AMPARs, resulting in long-lasting changes in synaptic strength.One important sub-family of AMPARs - the calcium-permeable AMPARs (CP-AMPARs) - plays a crucial role in many forms of synaptic plasticity. Their ability to allow calcium entry into cells is essential in triggering rapid chemical processes that cause long-term changes in AMPAR number, subtype and properties. In the healthy brain, activation and regulation of CP- AMPARs is a key part of normal transmission. However, forms of synaptic dysfunction that involve inappropriate calcium influx can be toxic. Indeed, failure to correctly regulate these CP-AMPARs underlies a number of neurodegenerative conditions, including neuron death following stroke, glial cell damage in infants starved of oxygen, and neuron loss in motor neuron disease. Increased expression of CP-AMPARs also underlies certain chronic pain syndromes and psychiatric disorders, including addiction. There is therefore an urgent need to understand the cellular and molecular mechanisms governing CP-AMPAR regulation - to reveal potential strategies that could be used in treatments. AMPAR properties are dictated by their core building blocks, and also by a large number of associated proteins, many of which have only recently been discovered. Our work, and that of close colleagues, has identified some of the protein partners governing the regulation of CP-AMPARs involved in normal synaptic plasticity, and in deleterious changes. One important recent discovery, highly relevant to our work, has been the identification of novel and exciting AMPAR subtype-selective drugs that act by targeting auxiliary proteins. These suppress transmitter activation of AMPARs only when the receptor is associated with a specific type of auxiliary protein. These drugs therefore offer a powerful means of identifying those types of auxiliary subunits involved in regulating detrimental forms of CP-AMPAR plasticity, and a means of selectively suppressing dysfunctional CP-AMPAR activity. At the same time, recent work on the structure of AMPARs physically associated with their auxiliary subunits offers the possibility of real insight into understanding the structure of the binding site occupied by these highly selective drugs.We plan to capitalise on these important new developments to elucidate the roles played by auxiliary subunits in CP-AMPAR plasticity in healthy brain, and in neurological disorders where regulation of CP-AMPARs appears to be a prominent feature. This will provide insight into ways in which harmful and damaging effects of CP-AMPAR plasticity may be suppressed or blocked.

我们所有的感觉、思想、动作、情绪和记忆都是由神经系统中神经元的电活动产生的。这些细胞之间的信息传递依赖于在特定的接触点-突触释放化学信号。在哺乳动物的大脑中，谷氨酸是主要的兴奋性递质，从一个神经元释放出来，激活嵌入相邻细胞突触后膜中的谷氨酸受体。通过这种方式，神经电脉冲在神经元之间传递。虽然大脑中存在几种不同类型的谷氨酸受体，但由一个家族-AMPA受体(AMPAR)-发出的信号对几乎所有大脑功能都是核心的，负责大多数快速的信号传递，以及与突触和电路功能变化密切相关的较长时间的过程。健康大脑的定义特征之一是它能够保留从经验中产生的信息。AMPAR属性的变化在这种记忆的形成过程中很重要。这一过程涉及AMPAR数量或效率的改变，导致突触强度的长期变化。AMPAR的一个重要亚家族-钙通透性AMPAR(CP-AMPAR)-在许多形式的突触可塑性中发挥着关键作用。它们允许钙进入细胞的能力是触发快速化学过程的关键，这些过程会导致AMPAR数量、亚型和特性的长期变化。在健康的大脑中，CP-AMPAR的激活和调节是正常传递的关键部分。然而，涉及不适当钙内流的各种形式的突触功能障碍可能是有毒的。事实上，未能正确地调节这些CP-AMPAR是许多神经退行性疾病的基础，包括中风后的神经元死亡，缺氧婴儿的神经胶质细胞损伤，以及运动神经元疾病中的神经元丢失。CP-AMPAR的表达增加也是某些慢性疼痛综合征和精神障碍的基础，包括成瘾。因此，迫切需要了解控制CP-AMPAR调控的细胞和分子机制，以揭示可能用于治疗的潜在策略。Ampar的特性由它们的核心构件决定，也由大量相关蛋白质决定，其中许多蛋白质是最近才被发现的。我们和亲密同事的工作已经确定了一些蛋白质伙伴，这些蛋白质伙伴调控CP-AMPAR参与正常突触可塑性和有害变化的调节。最近的一个重要发现，与我们的工作高度相关，是识别了新的和令人兴奋的AMPAR亚型选择性药物，这些药物通过靶向辅助蛋白发挥作用。只有当受体与特定类型的辅助蛋白相关时，它们才会抑制AMPAR的递质激活。因此，这些药物提供了一种强大的手段来识别参与调节有害形式的CP-AMPAR可塑性的那些类型的辅助亚基，并提供了一种选择性地抑制功能失调的CP-AMPAR活性的手段。同时，最近关于AMPAR与其辅助亚基物理相关的结构的工作为理解这些高选择性药物所占据的结合位点的结构提供了真正的洞察力。我们计划利用这些重要的新发展来阐明辅助亚基在健康大脑和神经疾病中所扮演的角色，在这些疾病中，CP-AMPAR的调节似乎是一个突出的特征。这将有助于深入了解如何抑制或阻止CP-AMPAR可塑性的有害和破坏性影响。

项目成果

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior.

• DOI: 10.1016/j.celrep.2021.109249
• 发表时间: 2021-06-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Magno L;Asgarian Z;Pendolino V;Velona T;Mackintosh A;Lee F;Stryjewska A;Zimmer C;Guillemot F;Farrant M;Clark B;Kessaris N
• 通讯作者: Kessaris N

An unexpected role for a glutamate receptor

谷氨酸受体的意想不到的作用

• DOI: 10.1126/science.adm6771
• 发表时间: 2023
• 期刊: Science
• 影响因子: 56.9
• 作者: Coombs I

Enhanced functional detection of synaptic calcium-permeable AMPA receptors using intracellular NASPM.

• DOI: 10.7554/elife.66765
• 发表时间: 2023-04-12
• 期刊: eLife
• 影响因子: 7.7
• 作者: Coombs I;Bats C;Sexton CA;Studniarczyk D;Cull-Candy SG;Farrant M
• 通讯作者: Farrant M

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment.

• DOI: 10.1111/epi.17419
• 发表时间: 2022-12
• 期刊: EPILEPSIA
• 影响因子: 5.6
• 作者: Coombs, Ian D.;Ziobro, Julie;Krotov, Volodymyr;Surtees, Taryn-Leigh;Cull-Candy, Stuart G.;Farrant, Mark
• 通讯作者: Farrant, Mark