A cytoplasmic region determines single-channel conductance in 5-HT3 receptors

Stephen P. Kelley, James I. Dunlop, Ewen F. Kirkness, Jeremy J. Lambert, John A. Peters

    Research output: Contribution to journalArticlepeer-review

    228 Citations (Scopus)

    Abstract

    5-Hydroxytryptamine type 3 (5-HT3) receptors are cationselective transmitter-gated ion channels of the Cys-loop superfamily1– 9. The single-channel conductance of human recombinant 5-HT3 receptors assembled as homomers of 5-HT3A subunits, or heteromers of 5-HT3A and 5-HT3B subunits, are markedly different, being 0.4 pS (refs 6, 9) and 16 pS (ref. 7), respectively. Paradoxically, the channel-lining M2 domain of the 5-HT3A subunit would be predicted to promote cation conduction, whereas that of the 5-HT3B subunit would not7. Here we describe a determinant of single-channel conductance that can explain these observations. By constructing chimaeric 5-HT3A and 5-HT3B subunits we identified a region (the ‘HA-stretch’)10 within the large cytoplasmic loop of the receptor that markedly influences channel conductance. Replacement of three arginine residues unique to the HA-stretch of the 5-HT3A subunit by their 5-HT3B subunit counterparts increased single-channel conductance 28-fold. Significantly, ultrastructural studies of the Torpedo nicotinic acetylcholine receptor11 indicate that the key residues might frame narrow openings that contribute to the permeation pathway. Our findings solve the conundrum of the anomalously low conductance of homomeric 5-HT3A receptors and indicate an important function for the HA-stretch in Cys-loop transmittergated ion channels.
    Original languageEnglish
    Pages (from-to)321-324
    Number of pages4
    JournalNature
    Volume424
    Issue number6946
    DOIs
    Publication statusPublished - Jul 2003

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