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

我们所有的感觉、思想、动作、情绪和记忆都是由我们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。在哺乳动物脑中，谷氨酸是主要的兴奋性递质，从一个神经元释放以激活嵌入相邻细胞的突触后膜中的谷氨酸受体。虽然大脑中存在几种不同类型的谷氨酸受体，但AMPA受体（AMPAR）家族的信号传导几乎对所有大脑功能都至关重要，负责最快速的信号传导，以及与突触和电路功能变化密切相关的长期过程。健康大脑的一个重要特征是它能够保留来自经验的信息。AMPAR特性的变化对这种记忆的形成很重要。AMPAR的一个重要亚家族--钙渗透性AMPAR（CP-AMPAR）--在许多形式的突触可塑性中起着至关重要的作用。它们允许钙进入细胞的能力在触发快速化学过程中至关重要，这些过程导致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输的关键部分。然而，涉及不适当的钙内流的突触功能障碍的形式可能是有毒的。事实上，未能正确调节这些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和运动神经元疾病中的神经元损失。CP-AMPAR的表达增加也是某些慢性疼痛综合征和精神疾病（包括成瘾）的基础。因此，迫切需要了解CP-AMPAR调控的细胞和分子机制，以揭示可用于治疗的潜在策略。AMPAR的特性是由其核心构建模块决定的，也是由大量相关蛋白决定的，其中许多蛋白是最近才发现的。我们的工作，以及亲密的同事，已经确定了一些蛋白质合作伙伴管理的正常突触可塑性和有害的变化中涉及的CP-AMPAR的调节。最近的一个重要发现，与我们的工作高度相关，是鉴定出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联时，它们才抑制AMPAR的递质激活。因此，这些药物提供了一种强有力的手段来鉴定参与调节有害形式的CP-AMPAR可塑性的辅助亚基的类型，以及选择性抑制功能失调的CP-AMPAR活性的手段。与此同时，最近关于AMPARs与其辅助亚基物理结合的结构的研究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实的见解。我们计划利用这些重要的新进展来阐明辅助亚基在健康大脑中CP-AMPAR可塑性中所起的作用，以及在CP-AMPAR的调节似乎是突出特征的神经障碍中。这将提供洞察CP-AMPAR可塑性的有害和破坏性影响可能被抑制或阻断的方式。

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.