INVESTIGADORES
BOUZAT Cecilia Beatriz
congresos y reuniones científicas
Título:
Exploring Activation and Modulation of Cys-loop Receptors as Drug Targets
Autor/es:
CECILIA BOUZAT
Lugar:
Salto
Reunión:
Congreso; Latin American Crosstalk Biophysics and Physiology; 2015
Resumen:
Cys-loop receptors are pentameric neurotransmitter-gated ion channels that include serotonin (5-HT3), nicotinic (AChR), GABA and glycine receptors. They are involved in a large number of physiological functions and neurological disorders. We have combined mutagenesis, patch-clamp recordings, single-channel kinetic analysis and in silico studies to delineate molecular mechanisms and structures underlying the activation process and drug modulation. Our results revealed unique features of the activation of 7 AChR, which is involved in cognition, learning and memory, and identified key regions involved in the functional connection between ACh binding and channel opening. By generating a model that describes activation of 5-HT3A receptors by partial agonists, we detected intermediate conformational states, which led to a novel concept of partial agonism. We also delineated mechanisms and sites of action of positive allosteric modulators (PAMs) of 7, which represent promising therapeutic tools for the treatment of schizophrenia and Alzheimer?s disease. We determined that different types of PAMs bind to different sites and enhance open-channel lifetime by different mechanisms. Deciphering the molecular basis underlying responses of Cys-loop receptors has implications for the design of novel and more specific therapeutic compounds. We determined the composition of C. elegans muscle AChRs and generated and analyzed transgenic worms carrying mutations in muscle AChR subunits, which mimic those found in patients suffering from congenital myasthenic syndromes (CMS). Our results indicated that C. elegans is a valid model for studying human CMSs and for drug screening.