Novel research with an eye on better treatment
NeuroCypres, a consortium of 21 leading European laboratories in the area of Cys-loop receptors (CLR), was awarded EUR 11 million by the European Union. Its work will not only increase the level of knowledge in this area but will lay the foundation for the future development and discovery of new drugs for this class of receptors. In its Seventh Research Framework Programme (FP7), the EU announced a call whose aim was 'to apply high-throughput approaches for structure-function analysis of membrane-transporters and channels [...].This should help to identify potential new target sites for drugs to alleviate the burden of diseases involving membrane-transporters and channels'. Answering the call, amongst others, was the NeuroCypres consortium which is led by Professor Guus Smit. What those of us who are not so knowledgeable about CLRs should know is that they are vitally important in the functioning of the peripheral and central nervous system. Muscle disorders, hyperexcitabiliy of the brain such as in epilepsy and nicotine addiction have all been linked to CLRs. Some CLR subunit genes also appear to be linked to psychiatric diseases, such as schizophrenia and addiction. NeuroCypres brings together the expertise of some of Europe's leading laboratories. Together they will create the critical mass of knowledge needed to take this next step in increasing our knowledge of CLR structure and function. Scientifically speaking, CLRs are a special superfamily of ligand-gated ion channels. These receptors share an overall protein architecture of five protein subunits with an ion channel that can open and close depending on ligand binding. Medicinal drugs ranging from tranquillizers and anticonvulsants like the benzodiazepines to anti-emetics have been developed that specifically target CLRs. All this makes CLRs very important in medicine, but scientists still need more information on these. For over 25 years scientists have not been able to reveal the 3D structure of the proteins at the atomic resolution needed for specifically targeted drug design. To this end, an important aim of the NeuroCypres project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, channel blockers and modulators. Such an achievement will reveal basic mechanisms of receptor functioning and open new avenues to rational drug design. Along with this, another aim of the project is to increase our understanding of receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. Once this knowledge is obtained, pharmaceutical manufacturers will be able to use this information to help refine their medicines. For example, data gathered here could potentially be used to help separate benzodiazepines into two distinct categories/groups: one that is used to treat anxiety and another used to induce sleep. Muscle relaxants could also be developed which only target muscular CLR subtypes, while simultaneously not mimicking the effects of nicotine, therefore reducing adverse effects on circulation during surgery. Professor Smit is a world-class leader in this subject area and has been acknowledged as such for his efforts back in 2001. 'In 2001,' he explains, 'my colleague Titia Sixma (NKI) and I managed to produce and crystallize the protein AChBP, a functional and structural mimic of the ligand binding domain of CLRs. This was a breakthrough and over the last five years considerable progress has been made in the understanding of parts of the crystal structure of CLRs, which facilitated research in this area tremendously.'