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Molecular Pharmacology

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Research ArticleArticle

Functional Roles of Aromatic Residues in the Ligand-Binding Domain of Cyclic Nucleotide-Gated Channels

Jun Li and Henry A. Lester
Molecular Pharmacology May 1999, 55 (5) 873-882;
Jun Li
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Henry A. Lester
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Abstract

The ligand-binding domains of cyclic nucleotide-gated (CNG) channels show sequence homology to corresponding region(s) of theEscherichia coli catabolite gene-activator protein (CAP) and to the regulatory subunit of cAMP-dependent or cGMP-dependent protein kinases. The structure of CAP and that of a cAMP-dependent protein kinases regulatory subunit have been solved, prompting efforts to generate structural models for the binding domains in CNG channel. These models explicitly predicted that an aromatic residue in the CNG channel aligning with leucine 61 of CAP forms an interaction with the bound cyclic nucleotide. We tested this hypothesis by site-directed mutagenesis in a rat olfactory channel (rOCNC1) and a bovine rod photoreceptor channel (Brcng). We found that mutations at this site had only weak effects that were not specific to the aromatic or the hydrophobic nature of the substituted residue. This result weakens the hypothesis of a strong or specific interaction at this site. We also separately mutated most of the other aromatic residues in the binding domain to alanine; most of these mutations resulted in channels that either did not function or had only minor changes in sensitivity. However, replacing tyrosine 565 with alanine (Y565A) in rOCNC1 increased agonist sensitivity by ∼10-fold and resulted in prominent spontaneous activities. Y565 presumably lies between two α helices in the binding domain; one of these, the C helix, probably rotates during channel activation. The position of Y565 at the “hinge” between the C helix and another portion of the binding domain, and the consequences of Y565 mutations, strongly suggest that this portion of the binding domain is involved in channel gating processes.

Footnotes

  • Send reprint requests to: Dr. Henry A. Lester, Division of Biology, 156-29, California Institute of Technology, Pasadena, CA 91125. E-mail: lester{at}caltech.edu

  • ↵1 Present address: Department of Genetics, Stanford University, 300 Pasteur Dr., M310, Stanford, CA 94305.

  • This research was supported by Grant NS11756 from the National Institutes of Health.

  • Abbreviations:
    CNG
    cyclic nucleotide-gated
    PKA
    protein kinase A
    CAP
    E. coli catabolite gene-activator protein
    rOCNC1
    rat olfactory channel
    Brcng
    bovine rod photoreceptor channel
    PKA-R1
    type 1 regulatory subunit of bovine cAMP-dependent protein kinase
    PCR
    polymerase chain reaction
    • Received June 2, 1998.
    • Accepted December 30, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (5)
Molecular Pharmacology
Vol. 55, Issue 5
1 May 1999
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Research ArticleArticle

Functional Roles of Aromatic Residues in the Ligand-Binding Domain of Cyclic Nucleotide-Gated Channels

Jun Li and Henry A. Lester
Molecular Pharmacology May 1, 1999, 55 (5) 873-882;

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Research ArticleArticle

Functional Roles of Aromatic Residues in the Ligand-Binding Domain of Cyclic Nucleotide-Gated Channels

Jun Li and Henry A. Lester
Molecular Pharmacology May 1, 1999, 55 (5) 873-882;
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