Identification of a pre-active conformation of a pentameric channel receptor

In the nervous system, proteins of the pLGIC family are found in the membrane that surrounds each neuron. These proteins have channels that can allow ions to pass through the membrane and are responsible for transmitting electrical signals from one neuron to the next. Small molecules called neurotransmitters interact with the pLGICs to open or close the ion channel. If the ability of the pLGIC channels to open is altered, it can lead to behavioral changes like addiction, or diseases such as schizophrenia or epilepsy. For a pLGIC channel to switch between the “open” and “closed” states, specific parts of the protein need to move in relation to each other. However, to study these transitions researchers have previously relied on comparing the three-dimensional structures of open and closed pLGICs extracted out of the cell membrane. Different techniques are needed to directly follow these movements within membranes. Bacteria also have proteins belonging to the pLGIC family, and Menny et al. have now investigated one such bacterial protein to understand how pLGICs open. First, a small fluorescent molecule that glows differently if the environment around it changes was attached to various parts of the bacterial channel. These fluorescent markers revealed how several parts of the protein move and they also made it possible to measure how quickly these movements take place. Some of these movements happen before the channel opens, suggesting that the activation of this pLGIC protein happens in stages and involves the protein adopting a temporary intermediate state. The next step will be to better understand the structure of the intermediate state, which could help us to understand how pLGICs work in the nervous systems of animals. In future this may aid the design of new drugs that can modify the activity of these channels in patients with neurological conditions or addictions.