PT  - JOURNAL ARTICLE
AU  - Leonardo Dionisio
AU  - Ignacio Bergé
AU  - Matías Bravo
AU  - María del Carmen Esandi
AU  - Cecilia Bouzat
TI  - Neurotransmitter GABA Activates Muscle but Not <em>α</em>7 Nicotinic Receptors
AID  - 10.1124/mol.114.095539
DP  - 2015 Mar 01
TA  - Molecular Pharmacology
PG  - 391--400
VI  - 87
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/87/3/391.short
4100  - http://molpharm.aspetjournals.org/content/87/3/391.full
SO  - Mol Pharmacol2015 Mar 01; 87
AB  - Cys-loop receptors are neurotransmitter-activated ion channels involved in synaptic and extrasynaptic transmission in the brain and are also present in non-neuronal cells. As GABAA and nicotinic receptors (nAChR) belong to this family, we explored by macroscopic and single-channel recordings whether the inhibitory neurotransmitter GABA has the ability to activate excitatory nAChRs. GABA differentially activates nAChR subtypes. It activates muscle nAChRs, with maximal peak currents of about 10% of those elicited by acetylcholine (ACh) and 15-fold higher EC50 with respect to ACh. At the single-channel level, the weak agonism is revealed by the requirement of 20-fold higher concentration of GABA for detectable channel openings, a major population of brief openings, and absence of clusters of openings when compared with ACh. Mutations at key residues of the principal binding-site face of muscle nAChRs (αY190 and αG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face (εG57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the α/δ interface. Interestingly, single-channel activity elicited by GABA is similar to that elicited by ACh in gain-of-function nAChR mutants associated to congenital myasthenic syndromes, which could be important in the progression of the disorders due to steady exposure to serum GABA. In contrast, GABA cannot elicit single-channel or macroscopic currents of α7 or the chimeric α7-serotonin-type 3 receptor, a feature important for preserving an adequate excitatory/inhibitory balance in the brain as well as for avoiding activation of non-neuronal receptors by serum GABA.