Abstract
The transduction of extracellular chemical signals into intracellular events relies on the communication between neighboring domains of membrane receptors. In the particular case of Cys-loop receptor channels, five short stretches of amino acids, one per subunit, link the extracellular and transmembrane domains in such a way that the ion permeability of the latter and the affinity for neurotransmitters of the former become tied to each other. Here, using direct functional approaches, we set out to understand the molecular bases of this crucial interdependence through the characterization of total loss-of-current mutations at the interface between domains. Our results indicate that domain-domain proximity plays a previously unnoticed critical role inasmuch as inserting a single residue in each linker rendered the two domains independent of each other. In marked contrast, loss-of-current mutations that leave the linkers' length unaltered did not compromise the interdomain coupling, but rather, seemed to cause agonist-bound closed receptors to desensitize without appreciably opening.