2024
The Journal of Physiology

An α7 nicotinic and GABAB receptor-mediated pathway controls acetylcholine release in the tripartite neuromuscular junction

Authors:

Konstantin Petrov, Oksana Lenina, Jacqueline Leroy, Véronique Bernard, Thibaut Germain, Charles Truong, Leniz Nurullin, Guzel Sibgatullina, Kinji Ohno, Dmitry Samigullin, Eric Krejci

Keywords:

acetylcholine; acetylcholinesterase; aminobutyric acid; neuromuscular junction; Acetylcholine; ACh; neuromuscular junction; NMJ; α7 nicotinic ACh receptor; nAChR; GABA; GABAB receptor; terminal Schwann cells; TSCs; AChE; muscle fatigue

Abstract:

Terminal Schwann cells (TSCs) are capable of regulating acetylcholine (ACh) release at the neuromuscular junction (NMJ). We have identified GABA as a gliotransmitter at mouse NMJs. When ACh activates α7 nicotinic ACh receptor (nAChRs) on TSCs, GABA is released and activates GABA_B receptors on the nerve terminal that subsequently reduce ACh release. Indeed, specific deletion of the α7 nAChR in TSCs or inhibition of the metabotropic GABA_B receptor prevents the reduction in the quantal content of the end-plate potential induced by cholinesterase inhibitors. The α7/GABA_B receptor-mediated pathway is activated when ACh that escapes from collagen Q (ColQ) anchored AChE in the synaptic cleft and from PRiMA-anchored butyrylcholinesterase on the TSC activates α7 nAChRs on the TSC. Consequently, prolonged tetanic stimulation of isolated muscle activates the α7/GABA_B receptor pathway, which reduces post-tetanic ACh release. When AChE levels are low in neonatal mice, the α7/GABA_B receptor-mediated pathway decreases ACh release and reduces ex vivo muscle fatigue. For ColQ-deficient mice where AChE is not clustered, the decrease in AСh release following activation of this pathway contributes to mouse fatigue in vivo.