Neurotransmitter GABA activates muscle but not alpha-7 nicotinic receptors

DIONISIO, LEONARDO; BERGÉ IGNACIO; BRAVO MATÍAS; ESANDI MARÍA DEL CARMEN; BOUZAT CECILIA

Congreso; XLIII Reunión Anual SAB 2014; 2014

Cys-loop receptors are neurotransmitter-activated ion channelsinvolved in synaptic and extrasynaptic transmission in the brainand are also present in non-neuronal cells. As GABAA and nicotinicreceptors (nAChR) belong to this family, we explored bymacroscopic and single-channel recordings if the inhibitoryneurotransmitter GABA has the ability to activate excitatorynAChRs. GABA differentially activates nAChR subtypes. Itactivates muscle nAChRs, with maximal peak currents of about 10% of those elicited by ACh and 15-fold higher EC50 with respect toACh. At the single-channel level, the weak agonism is revealed bythe requirement of 20-fold higher concentration of GABA fordetectable channel openings, a major population of brief openings,and absence of clusters of openings when compared to ACh.Mutations at key residues of the principal binding-site face ofmuscle nAChRs (alphaY190 and alphaG153) affect GABA-activationsimilarly as ACh-activation whereas a mutation at thecomplementary face (epsilonG57) shows a selective effect for GABA.Studies with subunit-lacking receptors show that GABA canactivate muscle nAChRs through the alpha/delta interface. Interestingly,single-channel activity elicited by GABA is similar to that elicited byACh in gain-of-function nAChR mutants associated to congenitalmyasthenic syndromes, which could be important in theprogression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel ormacroscopic currents of alpha-7 or the chimeric alpha-7-5HT3A receptor, afeature important for preserving an adequate excitatory/inhibitorybalance in the brain as well as for avoiding activation of nonneuronalreceptors by serum GABA