The Journal of General Physiology
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Published online
doi:10.1085/jgp.200709896
The Journal of General Physiology, Vol. 131, No. 2, 137-146
The Rockefeller University Press, 0022-1295 $30.00
© Jansen et al.
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ARTICLE

 Modular Design of Cys-loop Ligand-gated Ion Channels: Functional 5-HT3 and GABA {rho}1 Receptors Lacking the Large Cytoplasmic M3M4 Loop



Michaela Jansen, Moez Bali, and Myles H. Akabas

Department of Physiology and Biophysics, Department of Neuroscience, and Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461

Correspondence to Myles Akabas: makabas{at}aecom.yu.edu

Cys-loop receptor neurotransmitter-gated ion channels are pentameric assemblies of subunits that contain three domains: extracellular, transmembrane, and intracellular. The extracellular domain forms the agonist binding site. The transmembrane domain forms the ion channel. The cytoplasmic domain is involved in trafficking, localization, and modulation by cytoplasmic second messenger systems but its role in channel assembly and function is poorly understood and little is known about its structure. The intracellular domain is formed by the large (>100 residues) loop between the {alpha}-helical M3 and M4 transmembrane segments. Putative prokaryotic Cys-loop homologues lack a large M3M4 loop. We replaced the complete M3M4 loop (115 amino acids) in the 5-hydroxytryptamine type 3A (5-HT3A) subunit with a heptapeptide from the prokaryotic homologue from Gloeobacter violaceus. The macroscopic electrophysiological and pharmacological characteristics of the homomeric 5-HT3A-glvM3M4 receptors were comparable to 5-HT3A wild type. The channels remained cation-selective but the 5-HT3A-glvM3M4 single channel conductance was 43.5 pS as compared with the subpicosiemens wild-type conductance. Coexpression of hRIC-3, a protein that modulates expression of 5-HT3 and acetylcholine receptors, significantly attenuated 5-HT–induced currents with wild-type 5-HT3A but not 5-HT3A-glvM3M4 receptors. A similar deletion of the M3M4 loop in the anion-selective GABA-{rho}1 receptor yielded functional, GABA-activated, anion-selective channels. These results imply that the M3M4 loop is not essential for receptor assembly and function and suggest that the cytoplasmic domain may fold as an independent module from the transmembrane and extracellular domains.

Abbreviations used in this paper: CFFR, Ca2+-free frog Ringer buffer; 5-HT3A, 5-hydroxytryptamine type 3A; LGIC, ligand-gated ion channel; MA, membrane-associated; RT, room temperature.


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