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Molecular Pharmacology

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Research ArticleArticle

Involvement of Regions in Domain I in the Opioid Receptor Sensitivity of α1B Ca2+ Channels

Arthur A. Simen and Richard J. Miller
Molecular Pharmacology May 2000, 57 (5) 1064-1074;
Arthur A. Simen
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Richard J. Miller
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Abstract

The structural basis of Ca2+ channel inhibition by G proteins has received considerable attention recently, and multiple regions on Ca2+ channels that interact with G protein subunits have been identified. We have demonstrated previously that a region extending from the N terminus to the I/II loop of the Ca2+ channel is involved in determining the differences between α1B and α1E Ca2+ channels with respect to inhibition by G proteins. Here we explore this region of the channel in greater detail in an effort to further define the regions involved in determining inhibition. Chimeric Ca2+ channels constructed from α1B and α1E Ca2+ channels revealed that the N terminus, the I/II loop, and domain I all play an important role in determining inhibition. We identified a 70-amino acid fragment from domain I that mediates the effects of domain I, and a 50-amino acid fragment from the I/II loop that mediates the effects of the I/II loop. When these regions from α1B were exchanged into α1E, inhibition identical with that of α1B was observed. The differences between α1B and α1E in the identified region of domain I involve residues that are predicted to be almost exclusively extracellular. Mutations to some of the high-affinity G protein binding regions of α1B (α interaction domain, CC14, and a C-terminal Gα binding site) caused relatively little change in inhibition, which suggests that these sites are not necessary individually for G protein-mediated inhibition and may help to explain the small effects of exchanging these regions in isolation.

Footnotes

  • Send reprint requests to: Richard J. Miller, Ph.D., Dept. of Neurobiology, Pharmacology, and Physiology, University of Chicago, 947 East 58th Street, Chicago IL 60637. E-mail:rjmx{at}midway.uchicago.edu

  • This work was supported by National Institute of Health Grants DA02121, MH40165, NS33826, DK44840, and NS21442. A.A.S. was supported by Grants HD07009 and DA02575.

  • Abbreviations:
    DHP
    dihydropyridine
    norBNI
    nor-binaltorphimine
    AID
    α interaction domain
    ND1
    N-terminal domain I region
    GID
    G protein interaction domain
    κOR
    κ-opioid receptor
    • Received September 29, 1999.
    • Accepted February 3, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (5)
Molecular Pharmacology
Vol. 57, Issue 5
1 May 2000
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Research ArticleArticle

Involvement of Regions in Domain I in the Opioid Receptor Sensitivity of α1B Ca2+ Channels

Arthur A. Simen and Richard J. Miller
Molecular Pharmacology May 1, 2000, 57 (5) 1064-1074;

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Research ArticleArticle

Involvement of Regions in Domain I in the Opioid Receptor Sensitivity of α1B Ca2+ Channels

Arthur A. Simen and Richard J. Miller
Molecular Pharmacology May 1, 2000, 57 (5) 1064-1074;
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