HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain.

Abstract
Diminished inhibitory neurotransmission in the superficial dorsal horn of the spinal cord is thought to contribute to chronic pain. In inflammatory pain, reductions in synaptic inhibition occur partially through prostaglandin E2- (PGE2-) and PKA-dependent phosphorylation of a specific subtype of glycine receptors (GlyRs) that contain α3 subunits. Here, we demonstrated that 2,6-di-tert-butylphenol (2,6-DTBP), a nonanesthetic propofol derivative, reverses inflammation-mediated disinhibition through a specific interaction with heteromeric αβGlyRs containing phosphorylated α3 subunits. We expressed mutant GlyRs in HEK293T cells, and electrophysiological analyses of these receptors showed that 2,6-DTBP interacted with a conserved phenylalanine residue in the membrane-associated stretch between transmembrane regions 3 and 4 of the GlyR α3 subunit. In native murine spinal cord tissue, 2,6-DTBP modulated synaptic, presumably αβ heteromeric, GlyRs only after priming with PGE2. This observation is consistent with results obtained from molecular modeling of the α-β subunit interface and suggests that in α3βGlyRs, the binding site is accessible to 2,6-DTBP only after PKA-dependent phosphorylation. In murine models of inflammatory pain, 2,6-DTBP reduced inflammatory hyperalgesia in an α3GlyR-dependent manner. Together, our data thus establish that selective potentiation of GlyR function is a promising strategy against chronic inflammatory pain and that, to our knowledge, 2,6-DTBP has a unique pharmacological profile that favors an interaction with GlyRs that have been primed by peripheral inflammation.
AuthorsMario A Acuña, Gonzalo E Yévenes, William T Ralvenius, Dietmar Benke, Alessandra Di Lio, Cesar O Lara, Braulio Muñoz, Carlos F Burgos, Gustavo Moraga-Cid, Pierre-Jean Corringer, Hanns Ulrich Zeilhofer
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 7 Pg. 2547-60 (07 01 2016) ISSN: 1558-8238 [Electronic] United States
PMID27270175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Inflammation Mediators
  • Phenols
  • Receptors, Glycine
  • Recombinant Proteins
  • 2,6-di-tert-butylphenol
  • Phenylalanine
Topics
  • Allosteric Site
  • Animals
  • Female
  • HEK293 Cells
  • Humans
  • Hyperalgesia (metabolism)
  • Inflammation (metabolism)
  • Inflammation Mediators (metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Neurons
  • Pain
  • Pain Management (methods)
  • Phenols (chemistry)
  • Phenylalanine (chemistry)
  • Phosphorylation
  • Protein Conformation
  • Receptors, Glycine (metabolism)
  • Recombinant Proteins (chemistry)
  • Spinal Cord (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: