Involvement of regions in domain I in the opioid receptor sensitivity of α1B Ca2+ channels

Arthur A. Simen, Richard J. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 α1ECa2+ 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. Chimetic 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 α1 B (α interaction domain, 0014, 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.

Original languageEnglish (US)
Pages (from-to)1064-1074
Number of pages11
JournalMolecular pharmacology
Volume57
Issue number5
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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