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Phosphorylation state–dependent modulation of spinal glycine receptors alleviates inflammatory pain
Mario A. Acuña, … , Pierre-Jean Corringer, Hanns Ulrich Zeilhofer
Mario A. Acuña, … , Pierre-Jean Corringer, Hanns Ulrich Zeilhofer
Published June 6, 2016
Citation Information: J Clin Invest. 2016;126(7):2547-2560. https://doi.org/10.1172/JCI83817.
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Research Article Neuroscience

Phosphorylation state–dependent modulation of spinal glycine receptors alleviates inflammatory pain

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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.

Authors

Mario 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

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Figure 2

A molecular site for the actions of 2,6-DTBP on α3GlyRs.

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A molecular site for the actions of 2,6-DTBP on α3GlyRs.
(A) Concentrati...
(A) Concentration-response curves of glycine in wild-type and (F388A) point-mutated α3GlyRs. (B) Traces of glycine-activated whole-cell currents recorded from cells expressing wild-type or (F388A) point-mutated α3GlyRs in the absence or presence of 2,6-DTBP (100 μM). (C) Concentration-response curves of 2,6-DTBP for wild-type and (F388A) point-mutated α3GlyRs. (D) Examples of single-channel recordings from membranes expressing point-mutated (F388A) α3GlyRs in the presence or absence of 2,6-DTBP. (E) Ion channel nPo of the (F388A) α3GlyR in the absence or presence of 2,6-DTBP (10 μM). (F) Percentage change of nPo following the application of 2,6-DTBP in wild-type and (F388A) point-mutated α3GlyRs. ***P < 0.001, unpaired t test. All data are the mean ± SEM from 6 to 9 cells per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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