The Interface between Extracellular and Transmembrane Domains of Homomeric Cys-Loop Receptors Governs Open-Channel Lifetime and Rate of Desensitization

• Autores: Bouzat, Cecilia Beatriz; Bartos, Mariana; Corradi, Jeremias; Sine, Steven M.
• Año de publicación: 2008
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Acetylcholine; Chimeric; Receptors; Desensitization
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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 7 and 5-HT3A 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 7 receptors, agonist-evoked single-channel currents appear mainly as isolated brief openings (o 0.35 ms), whereas macroscopic currents after a step pulse of agonist desensitize rapidly (d 0.4 ms). In contrast for 5-HT3A receptors, agonist-evoked single-channel currents appear as clusters of many long openings in quick succession (cluster 1.2 s), whereas macroscopic currents desensitize slowly (d 1.1 s). A chimeric 7-5HT3A 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 7 and 5-HT3A receptors and that functional differences between the two receptors arise primarily through structural differences at the interface between extracellular and transmembrane domains.
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bartos, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Sine, Steven M.. Mayo Clinic College of Medicine; Estados Unidos