INVESTIGADORES
BOUZAT Cecilia Beatriz
congresos y reuniones científicas
Título:
Neurotransmitter-gated ion channels: On how structure relates to function
Autor/es:
BOUZAT C
Lugar:
PUERTO Varas.
Reunión:
Simposio; XII CongresoThe Pan-American Association for Biochemistry and Molecular Biology. Membrane Proteins.; 2013
Institución organizadora:
Latin American Protein Society
Resumen:
Neuronal alpha7 receptors participate in cognition, synaptic plasticity and neuroprotection.They belong to the family of pentameric neurotransmitter-gated ion channels, whichcontain a large extracellular domain that carries the agonist binding sites and atransmembrane 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 alpha7 contains five identical agonist binding sites, we explored how occupancy relates to open-channel stability. We found that alpha7 can elicit full biological responses with only one occupied binding site. This may adapt alpha7 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 alpha7 activity is associated with neurological and neurodegenerative disorders, and positive allosteric modulators (PAMs), which do not disrupt the temporal control provided by the neurotransmitter, areemerging as novel therapeutic tools. We have deciphered mechanisms and sites of actionof PAMs with the aim of contributing to rational drug design.