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

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

Research output: Contribution to journalArticle

99 Citations (Scopus)

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

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L-Type Calcium Channels
Mutation
Amino Acids
Mutagenesis
Tyrosine
1,4-dihydropyridine
Electric potential

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Peterson, Blaise ; Tanada, Timothy N. ; Catterall, William A. / Molecular determinants of high affinity dihydropyridine binding in L-type calcium channels. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 10. pp. 5293-5296.
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Molecular determinants of high affinity dihydropyridine binding in L-type calcium channels. / Peterson, Blaise; Tanada, Timothy N.; Catterall, William A.

In: Journal of Biological Chemistry, Vol. 271, No. 10, 08.03.1996, p. 5293-5296.

Research output: Contribution to journalArticle

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