Mechanisms of neurotransmitter receptor subunit compatibility

Pentameric ligand-gated ion-channels (pLGIC) are neurotransmitter receptors that mediate fast synaptic transmission and muscle contraction in all animals. Ligand binding allows either cations or anions to pass through the post-synaptic cell membrane and induce, or inhibit, muscle contraction, respectively. The pLGIC subunit family traces to before divergence of eukaryotes from prokaryotes and have since expanded to bind to a wide variety of ligands, while retaining a conserved structure. Understanding how the organization and function of pLGIC is regulated and how they evolve between different species is necessary to understand parasite anthelminthic resistance and its relation to model laboratory organisms. Duplication of a homomeric pLGIC, encoded by a single gene, to produce two different homomeric receptors, required an evolved mechanism of subunit exclusion to prevent the descendent gene products combining. This could be through physical, spacial, or temporal separation. Cel-ACR-20 and Cel-ACR-23 are paralogs that form homomeric betaine receptors in C. elegans targeted by the anthelmintic monepantel (MPTL). They are recent orthologs of Hco-mptl-1, also a homomeric, MPTL sensitive betaine receptor. It is unlikely that ACR-20 and ACR-23 form a heteromer in vivo since MPTL resistance maps to mptl-1 and acr-23, but not acr-20. This project investigates the physical interaction between ACR-20 and ACR-23 in Xenopus oocyte electrophysiology through affinity and gating properties of homomeric and heteromeric mixtures and the ability of one truncated subunit to reduce expression of the other.