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

Author

Listed:
  • Stephen P. Kelley

    (The University of Dundee)

  • James I. Dunlop

    (The University of Dundee)

  • Ewen F. Kirkness

    (The Institute for Genomic Research)

  • Jeremy J. Lambert

    (The University of Dundee)

  • John A. Peters

    (The University of Dundee)

Abstract

5-Hydroxytryptamine type 3 (5-HT3) receptors are cation-selective transmitter-gated ion channels of the Cys-loop superfamily1,2,3,4,5,6,7,8,9. 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 transmitter-gated ion channels.

Suggested Citation

  • Stephen P. Kelley & James I. Dunlop & Ewen F. Kirkness & Jeremy J. Lambert & John A. Peters, 2003. "A cytoplasmic region determines single-channel conductance in 5-HT3 receptors," Nature, Nature, vol. 424(6946), pages 321-324, July.
    • Handle: RePEc:nat:nature:v:424:y:2003:i:6946:d:10.1038_nature01788
    DOI: 10.1038/nature01788
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    Cited by:

    1. Christian J. G. Tessier & Johnathon R. Emlaw & Raymond M. Sturgeon & Corrie J. B. daCosta, 2023. "Derepression may masquerade as activation in ligand-gated ion channels," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Eric Gibbs & Emily Klemm & David Seiferth & Arvind Kumar & Serban L. Ilca & Philip C. Biggin & Sudha Chakrapani, 2023. "Conformational transitions and allosteric modulation in a heteromeric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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