Calcium Binding in the Pore of L-type Calcium Channels Modulates High Affinity Dihydropyridine Binding (*)

The pore-forming α1 subunit of L-type voltage-gated Ca channels contains a Ca-binding site that is allosterically coupled to the receptor site for dihydropyridine (DHP) Ca antagonists. Site-directed mutations of conserved Phe and Glu residues in the pore-lining SS1/SS2 segments greatly reduced Ca enhancement of DHP binding. Substitution of Phe-1013 in the α1 subunit from rabbit skeletal muscle (α) with Gly (F1013G) as in DHP-insensitive Ca channels caused a 4-fold decrease in sensitivity to Ca. Mutation of the Ca-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 Ca, respectively, as well as decreases in the maximal DHP binding affinities attained at optimal concentrations of Ca. DHP binding to the charge-reversal mutation, E1014K, had no sensitivity to Ca. Our results demonstrate that high affinity Ca binding to the Glu residues in the SS1/SS2 segments of domains III and IV of α 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 Ca ions at sites in the pore.

• Publication year

  1995

• Venue

  Journal of Biological Chemistry

• Publication date

  1995-08-04

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/JBC.270.31.18201PMID 7629136
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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