Deciphering the function of neurotransmitter-gated ion channels: From the molecular to the animal level

Abstract

Pentameric neurotransmitter-gated ion channels mediate rapid communication in the nervous system, and include nicotinic (AChR), GABA, glycine and 5-HT3A receptors. They are implicated in important physiological functions, in neurological disorders and they are targets of therapeutic drugs. Receptors are also present in nonneuronal cells and are highly conserved in nematodes, where they are targets of antiparasitic drugs. By combining mutagenesis, cellexpression, patch-clamp recordings and in silico studies we identified key regions involved in the functional connection between agonist binding and channel opening and we defined sites and mechanisms of drugs affecting receptor activation. This information provides a foundation for the understanding of synaptic responses and their modulation. We determined that lymphocytes have neuronal-like synaptic components and express GABAA and neuronal 7 AChRs, which emerge as potential targets for modulating the immune response. We deciphered the composition of C. elegans muscle AChRs and generated transgenic worms carrying mutations in muscle AChR subunits, which mimic those found in patients suffering from congenital myasthenic syndromes (CMS). We postulate that C. elegans is a valid model for studying human CMSs and for drug screening.