Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta-arrestin 2-dependent MAPK-mediated pathways

J Neurochem. 2008 Dec;107(6):1753-65. doi: 10.1111/j.1471-4159.2008.05745.x. Epub 2008 Nov 10.


GTP binding regulatory protein (G protein)-coupled receptors can activate MAPK pathways via G protein-dependent and -independent mechanisms. However, the physiological outcomes correlated with the cellular signaling events are not as well characterized. In this study, we examine the involvement of G protein and beta-arrestin 2 pathways in kappa opioid receptor-induced, extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated proliferation of both immortalized and primary astrocyte cultures. As different agonists induce different cellular signaling pathways, we tested the prototypic kappa agonist, U69593 as well as the structurally distinct, non-nitrogenous agonist, C(2)-methoxymethyl salvinorin B (MOM-Sal-B). In immortalized astrocytes, U69593, activated ERK1/2 by a rapid (min) initial stimulation that was sustained over 2 h and increased proliferation. Sequestration of activated Gbetagamma subunits attenuated U69593 stimulation of ERK1/2 and suppressed proliferation in these cells. Furthermore, small interfering RNA silencing of beta-arrestin 2 diminished sustained ERK activation induced by U69593. In contrast, MOM-Sal-B induced only the early phase of ERK1/2 phosphorylation and did not affect proliferation of immortalized astrocytes. In primary astrocytes, U69593 produced the same effects as seen in immortalized astrocytes. MOM-Sal-B elicited sustained ERK1/2 activation which was correlated with increased primary astrocyte proliferation. Proliferative actions of both agonists were abolished by either inhibition of ERK1/2, Gbetagamma subunits or beta-arrestin 2, suggesting that both G protein-dependent and -independent ERK pathways are required for this outcome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Animals, Newborn
  • Arrestins / metabolism*
  • Astrocytes / drug effects
  • Astrocytes / physiology*
  • Benzeneacetamides / pharmacology
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Proteins / metabolism*
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Pertussis Toxin / pharmacology
  • Pyrrolidines / pharmacology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / antagonists & inhibitors
  • Receptors, Opioid, kappa / physiology*
  • Time Factors
  • Transfection / methods
  • beta-Arrestin 2
  • beta-Arrestins


  • ARRB2 protein, human
  • Analgesics
  • Arrb2 protein, rat
  • Arrestins
  • Benzeneacetamides
  • Enzyme Inhibitors
  • Glial Fibrillary Acidic Protein
  • Pyrrolidines
  • RNA, Small Interfering
  • Receptors, Opioid, kappa
  • beta-Arrestin 2
  • beta-Arrestins
  • Green Fluorescent Proteins
  • Pertussis Toxin
  • GTP-Binding Proteins
  • Bromodeoxyuridine
  • U 69593