Molecular determinants of high affinity dihydropyridine binding in L-type calcium channels

Blaise Z. Peterson, Timothy N. Tanada, William A. Catterall

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The pore-forming α1 subunit of L-type voltage-gated Ca2+ channels is pharmacologically modulated by dihydropyridine (DHP) Ca2+ antagonists and agonists. Site-directed mutation of amino acids within transmembrane segments IIIS6 and IVS6 to those characteristic of DHP-insensitive channels revealed 2 mutations in IIIS6 (I1049F and I1052F) and 4 mutations in IVS6 (Y1365I, M1366F, I1372M, and I1373L) with increased K(D) values for (+)-[3H]PN200- 110 binding. A tyrosine residue (Y1048) in IIIS6 that is conserved between DHP-sensitive and -insensitive Ca2+ channels was also altered by mutagenesis. Y1048F had a K(D) for (+)-[3H]PN200-110 binding that was increased 12-fold, and Y1048A had a K(D) at least 1000-fold higher than that of wild-type. These results support the hypothesis that transmembrane segments IIIS6 and IVS6 both contribute critical amino acid residues to the DHP receptor site and that Tyr-1048 within transmembrane segment IIIS6 is required for high affinity DHP binding, even though it is conserved between DHP-sensitive and -insensitive Ca2+ channels.

Original languageEnglish (US)
Pages (from-to)5293-5296
Number of pages4
JournalJournal of Biological Chemistry
Volume271
Issue number10
DOIs
StatePublished - Mar 8 1996

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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