Crosstalk Between Cholinergic and Gabaergic Systems

BRAVO M; DIONISIO L,; SPITZMAUL, G; BOUZAT, C.

Huerta Grande, Córdoba

Congreso; I Reunión Conjunta de Neurociencias; 2009

Sociedad Argentina de Investigación en Neurociencias y Taller Argentino de Neurociencias

Crosstalk Between Cholinergic and Gabaergic Systems   Matías Bravo, Leonardo Dionisio, Guillermo Spitzmaul and Cecilia Bouzat Instituto de Investigaciones Bioquímicas de Bahía Blanca – Camino La Carrindanga Km 7- UNS/CONICET- Argentina   Cys-loop receptors are pentameric neurotransmitter-activated ion channels that mediate fast synaptic transmission throughout the nervous system. They include excitatory receptors, such as the nicotinic cholinergic (AChR) and serotonin type 3 receptors (5-HT3), and inhibitory receptors activated by GABA or glycine. Given the homology between members of this family we evaluated if GABAergic agonists can activate nicotinic cholinergic receptors. In the presence of GABA (> 1 µM), single-channel openings from the muscle AChR are readily detected. Even at high GABA concentrations, openings do not appear in typical clusters as observed in ACh-activated channels, indicating that GABA is a low-efficacy agonist. The presence of GABA does not affect the channel properties of ACh-activated channels. We also studied activation by GABA of muscle AChRs carrying a mutation in aG153, which has been shown to decrease the dissociation rate of ACh (Sine et al., 1995). GABA activation is enhanced in the aG153S and aG153E mutants, indicating that this residue is involved in the activation by both neurotransmitters. In silico studies show that in the muscle AChR, GABA docks into the ACh-binding site, though it interacts with different residues when compared to ACh. However, no docking into the binding site is observed in the a7 AChR, in agreement with the lack of activation.  In conclusion, we determine that GABA is not capable of activating neuronal a7 AChRs but it acts as a partial agonist of the muscle AChR.