Neurotransmitter-gated ion channels: On how structure relates to function

BOUZAT C

PUERTO Varas.

Simposio; XII CongresoThe Pan-American Association for Biochemistry and Molecular Biology. Membrane Proteins.; 2013

Latin American Protein Society

Neurotransmitter-gated ion channels: On how structure relates to function and drug modulation   Cecilia Bouzat Instituto de Investigaciones Bioquímicas de Bahía Blanca- UNS/CONICET-Bahía Blanca Argentina. E-mail: inbouzat@criba.edu.ar   Neuronal a7 receptors participate in cognition, synaptic plasticity and neuroprotection. They belong to the family of pentameric neurotransmitter-gated ion channels, which contain a large extracellular domain that carries the agonist binding sites and a transmembrane domain that forms the ion channel. We combined mutagenesis, cell-expression and patch-clamp recordings to decipher how agonist binding is coupled to channel opening. We identified a network of loops that relays structural changes from the binding site towards the channel, and also contributes to open-channel lifetime and desensitization. Thus, this coupling region controls the beginning and duration of a synaptic response. Because a7 contains five identical agonist binding sites, we explored how occupancy relates to open-channel stability. We found that a7 can elicit full biological responses with only one occupied binding site. This may adapt a7 to its physiological role, since it often localizes distal to sites of nerve-released ACh, binds ACh with low affinity, and thus it may operate with low agonist occupancy. Decreased a7 activity is associated with neurological and neurodegenerative disorders, and positive allosteric modulators (PAMs), which do not disrupt the temporal control provided by the neurotransmitter, are emerging as novel therapeutic tools. We have deciphered mechanisms and sites of action of PAMs with the aim of contributing to rational drug design.