Calcium binding in the pore of L-type calcium channels modulates high affinity dihydropyridine binding

Blaise Z. Peterson, William A. Catterall

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75 Scopus citations

Abstract

The pore-forming α1 subunit of L-type voltage-gated Ca2+ channels contains a Ca2+-binding site that is allosterically coupled to the receptor site for dihydropyridine (DHP) Ca2+ antagonists. Site-directed mutations of conserved Phe and Glu residues in the pore-lining SS1/SS2 segments greatly reduced Ca2+ enhancement of DHP binding. Substitution of Phe-1013 in the α1 subunit from rabbit skeletal muscle (α(1S)) with Gly (F1013G) as in DHP-insensitive Ca2+ channels caused a 4-fold decrease in sensitivity to Ca2+. Mutation of the Ca2+-binding residues Glu-1014 in domain III and Glu-1323 in domain IV to Gln (E1014Q and E1323Q) caused 11- and 35-fold decreases in sensitivity to Ca2+, respectively, as well as decreases in the maximal DHP binding affinities attained at optimal concentrations of Ca2+. DHP binding to the charge-reversal mutation, E1014K, had no sensitivity to Ca2+. Our results demonstrate that high affinity Ca2+ binding to the Glu residues in the SS1/SS2 segments of domains III and IV of α(1s) stabilizes the DHP receptor site in its high affinity state. We propose a three-state model in which the affinity for DHPs is dependent on the presence of 0, 1, or 2 bound Ca2+ ions at sites in the pore.

Original languageEnglish (US)
Pages (from-to)18201-18204
Number of pages4
JournalJournal of Biological Chemistry
Volume270
Issue number31
DOIs
StatePublished - Aug 4 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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