Sensitization of the Adenylyl Cyclase System in Cloned κ-Opioid Receptor-Transfected Cells Following Sustained Agonist Treatment : A Chimeric Study Using G Protein α_<i2>/α_q Subunits

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Author(s)

Abstract

Chronic and/or sustained opioid treatment has been shown to result in development of sensitization of the adenylyl cyclase (AC) system or cAMP overshoot. In this study, we investigated the molecular mechanism responsible for sensitization of the AC system using CHO cells co-expressing cloned κ-opioid receptor and some chimeric G protein α<SUB>i2</SUB>/α<SUB>q</SUB> subunits. In CHO cells co-expressing the κ-opioid receptor and pertussis toxin-insensitive chimeric α<SUB>i2</SUB>/α<SUB>q</SUB> subunits with α<SUB>i2</SUB> residues Met<SUP>244</SUP> - Asn<SUP>331</SUP>, despite pretreatment with pertussis toxin, acute treatment with the κ-opioid-receptor - selective agonist U69, 593 suppressed forskolin-stimulated cAMP accumulation, while sustained treatment with U69, 593 (4 h) induced cAMP overshoot over the naive level by the κ-opioid-receptor - selective antagonist norbinaltorphimine (sensitization of the AC system). On the other hand, in CHO cells co-expressing the κ-opioid receptor and pertussis toxin-insensitive chimeric α<SUB>i2</SUB>/α<SUB>q</SUB> subunits without α<SUB>i2</SUB> residues Met<SUP>244</SUP> - Asn<SUP>331</SUP>, pretreatment with pertussis toxin completely blocked these acute and sustained effects of U69, 593 on cAMP accumulation. These results suggested that the presence of the specific region of α<SUB>i2</SUB> (Met<SUP>244</SUP> - Asn<SUP>331</SUP>), which was reported to be responsible for the inhibition of AC, and continuous inhibition of AC by α<SUB>i2</SUB> is necessary for the development of sensitization.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 81(4), 353-361, 1999-12-01

    The Japanese Pharmacological Society

References:  37

Codes

  • NII Article ID (NAID)
    10008197587
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00215198
  • NDL Article ID
    4948536
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
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