Integrins regulate opioid receptor signaling in trigeminal ganglion neurons

K. A. Berg, G. Zardeneta, K. M. Hargreaves, W. P. Clarke, S. B. Milam

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

The binding of integrins to the extracellular matrix results in focal organization of the cytoskeleton and the genesis of intracellular signals that regulate vital neuronal functions. Recent evidence suggests that integrins modulate G-protein-coupled receptor (GPCR) signaling in hippocampal neurons. In this study we evaluated the hypothesis that integrins regulate the mu opioid receptor in rat trigeminal ganglion neurons. For these studies, primary cultures of adult rat trigeminal ganglion neurons were used to demonstrate the colocalization of β1 and β3 integrins with mu opioid receptor in caveolin-1-rich membrane fractions, and at focal adhesions sites generated by integrin ligand binding. Furthermore, we show that the mu opioid receptor agonist, DAMGO ([D-Ala2,N-MePhe4,Gly-ol5]enkephalin), inhibits cyclic AMP (cAMP) accumulation in response to prostaglandin E2 (PGE2) stimulation in bradykinin-primed, but not unprimed, cultured trigeminal ganglia neurons. Application of soluble GRGDS (Gly-Arg-Gly-Asp-Ser) peptides that bind specific integrins (i.e. RGD-binding integrins) completely abolished the DAMGO effect in bradykinin-primed trigeminal ganglia neurons, but did not alter bradykinin-mediated hydrolysis of phosphatidylinositol. Likewise, monospecific anti-β1 and anti-β3 integrin subunit antibodies blocked this DAMGO effect in bradykinin-primed trigeminal ganglia neurons. Indeed, application of anti-β1 integrin subunit actually reversed DAMGO signaling, resulting in increased cAMP accumulation in these cells. This suggests that the relative amounts of specific activated integrins at focal adhesions may govern signaling by the mu opioid receptor, perhaps by altering interactions with G proteins (e.g. Gαi vs. Gαs). Collectively, these data provide the first evidence that specific integrins regulate opioid receptor signaling in sensory neurons.

Original languageEnglish (US)
Pages (from-to)889-897
Number of pages9
JournalNeuroscience
Volume144
Issue number3
DOIs
StatePublished - Feb 9 2007

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Keywords

  • DAMGO
  • G-protein-coupled receptor
  • bradykinin
  • focal adhesions
  • sensory neurons
  • signal transduction

ASJC Scopus subject areas

  • Neuroscience(all)

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