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

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.