The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization

The lifetimes of activated postsynaptic receptor channels contribute to the efficiency of synaptic transmission. Here we show that structural differences within the interface dividing extracellular and transmembrane domains of homomeric α7 and 5-HT_3A receptors account for the large differences in open-channel lifetime and time of desensitization onset between these contrasting members of the Cys-loop receptor superfamily. For α7 receptors, agonist-evoked single-channel currents appear mainly as isolated brief openings (τ_o = 0.35 ms), whereas macroscopic currents after a step pulse of agonist desensitize rapidly (τ_d = 0.4 ms). In contrast for 5-HT_3A receptors, agonist-evoked single-channel currents appear as clusters of many long openings in quick succession (τ_cluster = 1.2 s), whereas macroscopic currents desensitize slowly (τ_d = 1.1 s). A chimeric α7-5HT_3A receptor exhibits functional properties intermediate between those of the parent receptors, but the functional signatures of each parent are reconstituted after substituting the major loops within the interface of the extracellular and transmembrane domains from the corresponding parent receptor. Furthermore, these structural loops contribute to open-channel lifetime and time of desensitization onset in a nonadditive manner. The results suggest that desensitization is the major determinant of the lifetimes of activated α7 and 5-HT_3A receptors and that functional differences between the two receptors arise primarily through structural differences at the interface between extracellular and transmembrane domains.