Crosstalk between cholinergic and GABAergic systems

BRAVO, MATIAS; DIONISIO, LEONARDO; SPITZMAUL, GUILLERMO; BOUZAT, CECILIA

Huerta Grande

Congreso; First Joint Meeting of the Argentine Society for Neurosciences (SAN) and the Argentina Workshop in Neurosciences (TAN); 2009

Sociedad Argentina de Neurociencias y Taller Argentino de Neurociencias

Cys-loop receptors are pentameric neurotransmitter-activated ion channels that mediate fast synaptic transmission throughout the nervous system. They include excitatory receptors, such us 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 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 alphaG153, which has been shown to decrease the dissociation rato of ACh (Sine et al., 1995). GABA activation is enhanced in the alphaG153S and alphaG153E mutants, indicating that this residue is involved in the activation by both neurotransmitters. In silico studies show that in 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 alfa7 AChR, in agreement with the lack of activation. In conclusion, we determine that GABA is not capable of activating neuronal alfa7 AChRs but it acts as a partial agonist of the muscle AChR.