Neurotransmitter GABA Activates Muscle but Notα7 Nicotinic Receptors

Abstract

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 GABA A 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 EC 50 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 (aY190 and aG153) affect GABA activation similarly as ACh activation, whereas a mutation at the complementary face («G57) shows a selective effect for GABA. Studies with subunit-lacking receptors show that GABA can activate muscle nAChRs through the a/d 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 singlechannel or macroscopic currents of a7 or the chimeric a7-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.

The pro-algesic effect of γ-aminobutyric acid (GABA) injection into the masseter muscle of healthy men and women

“…This may mean that much of the acute pain response evoked by glutamate when injected into the human masseter muscle is coded by the firing of Aδ afferent fibers and thus that GABA, through its stronger depolarizing action on myelinated fibers acts to increase pain intensity reports. A recent report also indicated that GABA has the ability to activate neuromuscular nicotinic receptors at high concentration, which could lead to low level muscle contraction [32]. In the present study, subjects commonly reported that the muscle felt tight after GABA and glutamate were co-injected.…”

Makaluvamine G from the Marine Sponge Zyzzia fuliginosa Inhibits Muscle nAChR by Binding at the Orthosteric and Allosteric Sites

“…Several nAChR ligands possess an affinity toward γ-aminobutiric acid receptors (GABA A R) and vice versa: d -tubocurarine and α-cobratoxin act on GABA A R with sub-micromolar affinity [ 23 ], bicuculline inhibits α9 nAChR [ 24 ], and even GABA itself activates muscle nAChR [ 25 ]. Therefore, testing MG action on GABA A R was an essential part of this study.…”