Structural Basis of Activation of Neurotransmitter-Gated IoN Channels

BOUZAT C

Salta

Conferencia; 3rd Latinamerican Protein Society Meeting; 2010

Latinamerican Protein Society - Sociedad Argentina de Biofisica (SAB)

Structural Basis of Activation of Neurotransmitter-Gated Ion Channels Cecilia Bouzat   Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB). UNS-CONICET. 8000 Bahía Blanca, Argentina. inbouzat@criba.edu.ar   Neurotransmitter-gated ion channels mediate rapid synaptic transmission throughout the nervous system. Cys-loop receptors are members of this superfamily, which includes nicotinic (AChR), 5-HT3, GABA and glycine receptors. They are homo- or hetero-pentameric proteins that contain an extracellular domain, which carries the neurotransmitter binding sites, and a transmembrane region, which forms the ion pore. Their essential function is to couple the binding of the agonist at the extracellular domain to the opening of the pore. This process, which is known as gating, has not been elucidated. How structural changes are first elicited by agonist binding and then propagated through a distance of 50 Å to the gate within the pore is therefore central for the understanding of receptor function. Key domains involved in channel gating are the binding site, the interface between the extracellular and transmembrane domains, and the pore. We have combined mutant and chimeric receptors with pharmacological, electrophysiological and in silico studies to identify structures at the binding site and at the interface that govern channel gating in AChR and 5-HT3A receptors. We demonstrated that the interface consists of a network of interacting loops that relays structural changes from the binding site towards the pore, thus controlling the beginning and duration of the synaptic response. By applying an electrical fingerprinting strategy we determined that in homomeric Cys-loop receptors occupancy of three of the five identical binding sites is required for appropriate gating, and we identified key determinants of drug selectivity located at the binding sites.  Our results provide new information for the development of novel drugs that target Cys-loop receptors, which are affected in many neurological diseases. Supported by grants from CONICET, FONCYT, UNS.