Chimeric mutations in the M2 segment of the 5-hydroxytryptamine-gated chloride channel MOD-1 define a minimal determinant of anion/cation permeability

Claudine Menard, H. Robert Horvitz, Stephen Cannon

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The ionic selectivity of ligand-gated ion channels (LGICs) determines whether receptor activation produces an excitatory or inhibitory response. The determinants of anion/cation selectivity were investigated for a new member of the LGIC superfamily, MOD-1, a serotonin-gated chloride channel cloned from the nematode Caenorhabditis elegans. In common with other anionic LGICs (glycine receptors and GABAA receptors), the selectivity triple mutant in the pore-forming M2 segment (proline insertion, Ala → Glu substitution at the central ring, and Thr → Val at the hydrophobic ring) converted the selectivity of MOD-1 from anionic to cationic. Unlike other LGICs, however, this mutant in MOD-1 was highly selective for K+ over other cations. Subsets of this selectivity triple mutant were studied to define the minimal change required for conversion from anion-permeable to cation-permeable. The double mutant at the central ring of charge (ΔPro-269/A270E) produced a non-selective cation channel. Charge reversal at the central ring alone (A270E) was sufficient to convert MOD-1 to cation-permeable. These results refine the determinants of ion-charge selectivity in LGICs and demonstrate the critical role of the central ring of charge formed by the M2 segments.

Original languageEnglish (US)
Pages (from-to)27502-27507
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number30
DOIs
StatePublished - Jul 29 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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