Effects of the alkylating agent EEDQ on regulatory G proteins and recovery of agonist and antagonist alpha2-adrenoceptor binding sites in rat brain

Eur J Pharmacol. 1998 Jun 12;351(1):145-54. doi: 10.1016/s0014-2999(98)00295-7.


The aim of this study was to assess the effect of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced alpha2-adrenoceptor inactivation on regulatory G proteins and the recovery of agonist and antagonist binding sites. EEDQ induced a rapid increase in the abundance of rat brain cortical Galphai1/2 proteins (30% at 6 h) which reached a maximum at 4 days (45%) and which then slowly returned (7-30 days) to control values. EEDQ did not alter significantly the levels of Galphai3 and Galphao proteins. By using the standard monoexponential model, the analysis of the recovery of alpha2-adrenoceptor density (6 h-30 days) with [3H]UK 14304 (bromoxidine) and [3H]RX 821002 (2-metoxy idazoxan) in the cerebral cortex did not reveal differences in receptor turnover parameters. However, the recovery of [3H]UK 14304 binding fitted best to a new biphasic recovery model, suggesting the existence of two distinct phases of recovery of agonist sites (r1 and r2 = 15.7 and 7.4 fmol mg protein(-1) day(-1); k1 and k2 = 0.51 and 0.25 day(-1); (t1/2)1 and (t1/2)2 = 1.4 and 2.7 days). In contrast, the recovery of [3H]RX 821002 antagonist sites did not fit to the biphasic model (r = 8.1, k = 0.14, t1/2 = 4.9). Because agonist binding requires coupling to G proteins, the present results suggest that the rapid over-expression of Galphai1/2 proteins induced by EEDQ is related to the biphasic recovery of [3H]UK 14304 binding. The possible implication of the faster recovery of alpha2-adrenoceptor function after EEDQ inactivation is discussed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists*
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic alpha-Antagonists / pharmacology
  • Alkylating Agents / pharmacology*
  • Animals
  • Brimonidine Tartrate
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • Idazoxan / analogs & derivatives
  • Idazoxan / pharmacology
  • Male
  • Quinolines / pharmacology*
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley


  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Alkylating Agents
  • Quinolines
  • Quinoxalines
  • Brimonidine Tartrate
  • EEDQ
  • 2-methoxyidazoxan
  • GTP-Binding Proteins
  • Idazoxan