The structural basis of function in Cys - loop receptors

Cys-loop receptors are membrane-spanning neurotransmitter-gated ion channelsthat are responsible for fast excitatory and inhibitory transmission in the peripheral and centralnervous systems. The best studied members of the Cys-loop family are nACh, 5-HT3,GABAAand glycine receptors. All these receptors share a common structure of five subunits,pseudo-symmetrically arranged to form a rosette with a central ion-conducting pore. Some arecation selective (e.g. nACh and 5-HT3) and some are anion selective (e.g. GABAAand glycine).Each receptor has an extracellular domain (ECD) that contains the ligand-binding sites,a transmembrane domain (TMD) that allows ions to pass across the membrane, and anintracellular domain (ICD) that plays a role in channel conductance and receptor modulation.Cys-loop receptors are the targets for many currently used clinically relevant drugs(e.g. benzodiazepines and anaesthetics). Understanding the molecular mechanisms of thesereceptors could therefore provide the catalyst for further development in this field, as well aspromoting the development of experimental techniques for other areas of neuroscience.In this review, we present our current understanding of Cys-loop receptor structure andfunction. The ECD has been extensively studied. Research in this area has been stimulated inrecent years by the publication of high-resolution structures of nACh receptors and relatedproteins, which have permitted the creation of many Cys loop receptor homology models ofthis region. Here, using the 5-HT3 receptor as a typical member of the family, we describe howhomology modelling and ligand docking can provide useful but not definitive information aboutligand interactions. We briefly consider some of the many Cys-loop receptors modulators.We discuss the current understanding of the structure of the TMD, and how this links to theECD to allow channel gating, and consider the roles of the ICD, whose structure is poorlyunderstood. We also describe some of the current methods that are beginning to reveal thedifferences between different receptor states, and may ultimately show structural details oftransitions between them