RGSZ2 binds to the neural nitric oxide synthase PDZ domain to regulate mu-opioid receptor-mediated potentiation of the N-methyl-D-aspartate receptor-calmodulin-dependent protein kinase II pathway

Antioxid Redox Signal. 2011 Aug 15;15(4):873-87. doi: 10.1089/ars.2010.3767. Epub 2011 May 19.


Morphine increases the production of nitric oxide (NO) via the phosphoinositide 3-kinase/Akt/neural nitric oxide synthase (nNOS) pathway. Subsequently, NO enhances N-methyl-D-aspartate receptor (NMDAR)/calmodulin-dependent protein kinase II (CaMKII) cascade, diminishing the strength of morphine-activated Mu-opioid receptor (MOR) signaling. During this process, NO signaling is restricted by the association of nNOS to the MOR.

Aims: Here, we examined how nNOS/NO signaling is downregulated by the morphine-activated MOR and how this regulation affects antinociception.

Results: Accordingly, we show that the MOR-NMDAR regulatory loop relies on the negative control of nNOS activity exerted by RGSZ2, a protein physically coupled to the MOR. This regulation requires binding of the nNOS N terminal PDZ domain to the RGSZ2 PDZ binding motifs that lie upstream of the RGS box.

Innovation: Indeed, in RGSZ2-deficient mice morphine over-stimulates the nNOS/NO/NMDAR/CaMKII pathway, causing analgesic tolerance to develop rapidly. Recovery of RGSZ2 levels or inhibition of nNOS, protein kinase C, NMDAR, or CaMKII function restores MOR signaling and morphine recovers its full analgesic potency.

Conclusion: This RGSZ2-dependent regulation of NMDAR activity is relevant to persistent pain disorders associated with heightened NMDAR-mediated glutamate responses and the reduced antinociceptive capacity of opioids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Drug Tolerance
  • Male
  • Metabolic Networks and Pathways
  • Mice
  • Molecular Sequence Data
  • Morphine / pharmacology*
  • Nerve Tissue Proteins / metabolism
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / metabolism*
  • PDZ Domains
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism
  • Signal Transduction


  • Analgesics, Opioid
  • Hint1 protein, mouse
  • Nerve Tissue Proteins
  • RGS Proteins
  • RGS17 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, mu
  • Nitric Oxide
  • Morphine
  • Nitric Oxide Synthase Type I
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2