Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been highly conserved throughout evolution and play key roles in numerous physiological and pathological processes in humans. In the central nervous system, nAChRs have important roles in diverse processes including learning, memory and attention. Alterations of nAChR-related signalling contribute to neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease. In the peripheral nervous system, nAChRs are responsible for the fast-excitatory neurotransmission at neuromuscular junctions. At the neuromuscular junction, AChRs are localized at the surface of the muscles where they are activated by the release of acetylcholine from motoneuron. Activation of AChRs eventually trigger muscle contraction and then malfunction of AChRs lead to severe neuromuscular diseases such as myasthenia gravis or congenital myasthenic syndrome.
The free-living nematode worm Caenorhabditis elegans is a powerful model organism to study neuromuscular system and AChR function. In C. elegans, as in mammals, acetylcholine is the neurotransmitter used to trigger muscle contraction. A subclass of AChR present at the neuromuscluar junction has been well studied due to its sensitivity to levamisole, a nematode-specific agonist . Prolonged exposure to levamisole causes hyperactivation of AChR and then hypercontraction of C. elegans muscles leading to paralysis and eventually death of worms. However, mutations in genes regulating AChR biosynthesis, activity or clustering modify the response of the worms to levamisole.
As wild-type worms, the mutant worms initially paralysed when exposed to levamisole but after several hours they remain hypercontracted and start to move again. At the molecular level, this hypercontraction of adapting worms is characterized by a sustained elevated level of calcium in the muscle which is not observed in wild-type animals.
This project aimed to characterize the mechanisms that allow adapting worms to overcome the stress induced by sustained hypercontraction of muscle cells and to recover locomotion in a such situation. More generally, the goal is to study the mechanisms underlying the adaptation of striated muscle cells to the stress triggered by muscle hyperactivity.
