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The Journal of Neuroscience, July 30, 2008, 28(31):7808-7819; doi:10.1523/JNEUROSCI.0448-08.2008

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

Cecilia Bouzat,¹ Mariana Bartos,¹ Jeremías Corradi,¹ and Steven M. Sine²

¹Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur–Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca 8000, Argentina, and ²Receptor Biology Laboratory, Departments of Physiology and Biomedical Engineering and Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Correspondence should be addressed to either of the following: Dr. Cecilia Bouzat, Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur–Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca 8000, Argentina, Email: inbouzat{at}criba.edu.ar; or Dr. Steven M. Sine, Mayo Clinic College of Medicine, Rochester, MN 55905, Email: sine{at}mayo.edu

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-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 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-HT_3A 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 7-5HT_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 7 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.

Key words: nicotinic receptor; Cys-loop receptor; patch-clamp; desensitization; ion channel; chimera

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Received Jan. 31, 2008; revised May 2, 2008; accepted May 5, 2008.

Correspondence should be addressed to either of the following: Dr. Cecilia Bouzat, Instituto de Investigaciones Bioquímicas, Universidad Nacional del Sur–Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca 8000, Argentina, Email: inbouzat{at}criba.edu.ar; or Dr. Steven M. Sine, Mayo Clinic College of Medicine, Rochester, MN 55905, Email: sine{at}mayo.edu

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