doi: 10.1089/ars.2014.5993. Epub 2015 Feb 18.
The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control
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- PMID:25557043
- PMCID: PMC4367239
- DOI: 10.1089/ars.2014.5993
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The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control
María Rodríguez-Muñoz et al. Antioxid Redox Signal..
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Abstract
Aims: The in vivo pharmacology of the sigma 1 receptor (σ1R) is certainly complex; however, σ1R antagonists are of therapeutic interest, because they enhance mu-opioid receptor (MOR)-mediated antinociception and reduce neuropathic pain. Thus, we investigated whether the σ1R is involved in the negative control that glutamate N-methyl-d-aspartate acid receptors (NMDARs) exert on opioid antinociception.
Results: The MOR C terminus carries the histidine triad nucleotide-binding protein 1 (HINT1) coupled to the regulator of G-protein signaling RGSZ2-neural nitric oxide synthase assembly. Activated MORs stimulate the production of nitric oxide (NO), and the redox zinc switch RGSZ2 converts this signal into free zinc ions that are required to recruit the redox sensor PKCγ to HINT1 proteins. Then, PKCγ impairs HINT1-RGSZ2 association and enables σ1R-NR1 interaction with MOR-HINT1 complexes to restrain opioid signaling. The inhibition of NOS or the absence of σ1Rs prevents HINT1-PKCγ interaction, and MOR-NMDAR cross-regulation fails. The σ1R antagonists transitorily remove the binding of σ1Rs to NR1 subunits, facilitate the entrance of negative regulators of NMDARs, likely Ca(2+)-CaM, and prevent NR1 interaction with HINT1, thereby impairing the negative feedback of glutamate on opioid analgesia.
Innovation: A redox-regulated process situates MOR signaling under NMDAR control, and in this context, the σ1R binds to the cytosolic C terminal region of the NMDAR NR1 subunit.
Conclusion: The σ1R antagonists enhance opioid analgesia in naïve mice by releasing MORs from the negative influence of NMDARs, and they also reset antinociception in morphine tolerant animals. Moreover, σ1R antagonists alleviate neuropathic pain, probably by driving the inhibition of up-regulated NMDARs.
Figures
The σ1R in the cell membrane: interaction with the glutamate NMDAR. (A) The protein domains of the murine σ1R and of the NMDAR NR1 cytosolic C terminal sequence. The long isoform of σ1R contains 223 residues, with two hydrophobic TMs, TM1 and TM2. The hairpin loop contains a SIM 61–65 within a HR and a SANR. The C-terminal domain comprises another HR, which includes cholesterol-binding motifs (CRM1 and CRM2), a PMAR, and SBDLII. The NMDAR NR1 subunit C terminus C0-C1-C2 contains 104 residues with two HRs (HR1 and HR2; Lasergene Protean Software DNASTAR, Inc., Madison, WI).(B) The σ1Rcd region, charge average, and hydrophobicity map (the images were created using Lasergene Protean Software). The binding of this region to Bip is regulated through calcium (* taken from Ref. 43), and the SBDLII associates with SBDLI in the TM2 domain, forming the neurosteroid-binding pocket.(C) The binding of recombinant σ1R long and short forms to GST-NR1 C0-C1-C2. The recombinant NR1 C-terminal sequence C0-C1-C2 and σ1 receptor variants were used at 100 nM. The assay was performed in the presence or absence of 2.5 mM calcium. The bait protein (GST-NR1 C0-C1-C2) was immobilized by covalent attachment to NHS-activated sepharose. The prey proteins alone did not bind to either NHS-sepharose (negative control) or recombinant GST (negative control). After incubation, the proteins were resolved by SDS-PAGE chromatography, followed by Western blotting analysis. P stands for the precipitation of immobilized NR1 C-terminal sequences.(D) The proposed arrangement of the long σ1R in the cell membrane is shown with the loop directed to the cytosol, the cd HR situated in the inner region of TM1 and TM2, and the N- and C-terminal regions arranged toward the extracellular space, key indicates amino acid charge. σ1R, sigma 1 receptor; cd, C-terminal domain; H, helical region; HR, hydrophobic region; NMDAR, glutamateN-methyl-D-aspartate acid receptor; PMAR, potential membrane attachment region; SANR, sumo-associated negative region; SBDLII, steroid-binding-like domain II; SDS-PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis; SIM, SUMO-interacting motif; SUMO, small ubiquitin-related modifier; TM, transmembrane. To see this illustration in color, the reader is referred to the web version of this article atwww.liebertpub.com/ars
Interference assay of the association between NR1 C0-C1 and σ1R, HINT1 and CaM. A series of overlapping peptides (30 μM) mapping the C0 and C1 region (834–903) of NR1 subunits were incubated with 100 nM σ1R, 200 nM HINT1, or 100 nM Ca2+-CaM before the addition of 100 nM NR1. The NR1 was precipitated, and the associated protein was evaluated through ECL-densitometry. These data were obtained from three independent assays. *Significantly different from the σ1R or HINT1 signals in the absence of interfering peptides, ANOVA-Student–Keuls test;p<0.05. The peptide mapping regions that were tentatively implicated in the interaction of NR1 C0-C1 with these proteins are indicated in bold. Ca2+-CaM basal binding was low and greatly increased in the presence of peptides mapping to the HR1 and HR2 of NR1 subunits. This binding was abrogated when NR1 was sequentially incubated with peptides 4 and 10 before adding Ca2+-CaM. To increase the readability, the frames indicate higher exposition of the blots. The potential regions of Ca2+-CaM binding to the NR1 C0-C1 are indicated (Calmodulin Target Database;http://calcium.uhnres.utoronto.ca/ctdb/ctdb/sequence.html ). Amino acid charge, see key in Fig. 1D. HINT1, histidine triad nucleotide-binding protein 1. To see this illustration in color, the reader is referred to the web version of this article atwww.liebertpub.com/ars
Juxtaposition of the σ1R and NR1 C0-C1 regions based on their charge complementarities and hydrophobicity. (A) Proposed interaction of the σ1R loop with the NMDAR NR1 C0-C1 region. The discontinuousyellow frame indicates possible hydrophobic interactions. TM stands for transmembrane region. Thearrows on the NR1 sequence suggest a possible intramolecular interaction between the HR1 and HR2 hydrophobic regions (Lasergene Protean V8 DNASTAR).(B) Influence of SUMO1 on the σ1R association with NR1 subunits. The recombinant σ1R protein (100 nM) was preincubated with agarose-SUMO1. After the removal of the free σ1Rs, the NR1 subunits (100 nM) were added to the incubation milieu. In a set of assays, preformed agarose-NR1-σ1R complexes (100 nM) were incubated with free SUMO1. The agarose pellets containing the bound proteins were analyzed by Western blotting.(C) Model describing the potential interaction regions of the complete σ1R with NR1 C0-C1 segments.Closed boxes indicate charge complementarities, andopen boxes indicate potential hydrophobic interaction. Thearrows connect the HR on NR1 C0 with another region in σ1Rcd corresponding to SBDLII, a negative region that could bind calcium. TM stands for transmembrane domain, and the helix organization (H2–H5) is taken from Ortega-Roldanet al. (43). Key indicates amino acid charge for NR1 and s1R.(D) Diagram of calcium-dependent σ1R binding to the NR1 C terminal C0-C1 region. The σ1R loop in the cell membrane is oriented toward the cytosolic side, and both the N and C terminal sequences face the extracellular space. The hydrophobic cd region is oriented toward the inner side of the membrane and between the TM domains, forming the ligand-binding pocket. This hydrophobic and negative cd region interacts with a positive region of the σ1R loop. The position of certain residues is indicated in the figure. On calcium binding, this negative cd region becomes neutral and subsequently releases the positive loop region to bind other proteins, such as the NR1 subunit. Peptide interference mapping suggests that the NR1 HR1 and HR2 hydrophobic regions establish an intramolecular interaction. The calcium-bound σ1Rcd region would disrupt this internal interaction to bind to the NR1 subunit.
Co-localization of the NMDAR NR1 subunit with σ1R and MOR in the mouse PAG.Upper panel, Original Cajal drawing showing cells of the PAG, Golgi method. A, cerebral aqueduct; cell shape is varied, with predominance of the fusiform type, and the orientation is oblique or transversal. Mouse PAG (yellow dotted circle) and Coronal drawing of mouse brain showing the PAG region analyzed in this triple co-localization of σ1R, NMDAR NR1 subunit and MOR (red square in the diagram).Middle panel, Confocal laser-scanning microphotographs taken from coronal histological sections (10 μm) through the midbrain PAG showing individual labeling for σ1R (green), NR1 (red), and MOR (blue) antigens. Immunoreactivity was visualized with Alexa Fluor 488, 555 and 647, respectively.Lower panel, Triple co-localization of the MOR, σ1R, and NR1 subunits could be observed at the cell periphery and fibers (nuclei were removed). There was a high degree of coincidence between NR1 and σ1R (yellow color). The MOR co-localizes with σ1R (light green color) and NR1 (purple color) in a discrete pattern. Notice that high-power magnificationpanels show triple-co-localization aswhite structures (red arrows; for details, see Materials and Methods section and Supplementary Fig. S3). MOR, mu-opioid receptor; PAG, periaqueductal grey.
Effect of icv σ1R ligands on the morphine supraspinal analgesia and NMDAR activity. (A) Influence of the interval between the selective antagonist of σ1R, S1RA, and morphine in the production of analgesia. Mice received icv 3 nmol S1RA at the indicated time intervals before 3 nmol morphine, and analgesia was evaluated in the thermal (water 52°C) “tail-flick” test 30 min later. The bars represent the mean±SEM of the data from six mice. *Significantly different from the group that received only morphine,p<0.05. A series of σ1R antagonists and the agonist PRE084 were icv-injected at 30 min before 3 nmol morphine, and antinociception was evaluated at the indicated postopioid intervals. Each point represents the mean±SEM of data from 10 mice. The area under the curve in the postmorphine interval at 15–90 min was calculated using the trapezoidal rule for each σ1R ligand and dose (Sigmaplot/Sigmastat v12.5, Erkrath, Germany). *The analgesia produced by the σ1R antagonist-morphine combination was significantly different from that of morphine alone, ANOVA-Student–Newman–Keuls,p<0.05. The σ1R agonist PRE084 prevented S1RA from enhancing morphine analgesia. Mice received a combined injection of 3 nmol PRE084 and 3 nmol S1RA 30 min before morphine treatment. *Significantly different from the group that received vehicle and morphine or PRE084+S1RA and morphine,p<0.05.(B) The neurosteroids PG, PN, PN acetate, and PN sulfate (sulf) were used at 3 nmol, icv. The enhancing effects of progesterone on morphine analgesia were abolished by pregnenolone sulfate. *Significantly different from the group that received morphine and vehicle instead of the neurosteroid,p<0.05.(C) The selective σ1R antagonist S1RA impairs the MOR-mediated activation of NMDARs. Groups of 42 mice each received an icv dose of 10 nmol morphine alone or 3 nmol S1RA 30 min before the opioid. Control mice were treated with saline instead of morphine. Subsequently, for each group, six mice were sacrificed at the indicated intervals. PAG synaptosomes were obtained to determineex vivo the presence of CaMKII P-Thr286, NR1 C1 P-Ser890, and NR2A P-Tyr 1325. The MOR proteins were immunoprecipitated, and the associated NR1 subunits were determined by Western blotting. Immunosignals (average optical density of the pixels within the object area/mm2, Quantity One Software; Bio-Rad, Madrid, Spain) were expressed as the change relative to the control group (attributed an arbitrary value of 1,dashed lines). Each bar represents the mean±SEM of the data from three determinations that were performed using different gels and blots. *For every postopioid interval, indicates that S1RA produced a significant difference from the group receiving only morphine,p<0.05. We observed no differences in the levels of the nonphosphorylated proteins. Representative blots are shown in Supplementary Figure S4. The diagram indicates that S1RA impairs the MOR to NMDAR pathway, which is required to build up the negative feedbackvia kinases such as CaMKII on opioid signaling. icv, intracerebroventricular; PG, progesterone; PN, pregnenolone.
Influence of the interval S1RA-morphine on the MOR-induced activation of NMDARs. (A) Influence of the interval S1RA-morphine. Groups of 36 mice each received icv a desensitizing dose of 10 nmol morphine alone or 3 nmol S1RA at 10, 30 min, 1, 3, or 24 h before the administration of the opioid. Subsequently, for each group receiving morphine, six mice were sacrificed at 90 min, 6, or 24 h after opioid treatment. The control mice received saline instead of morphine. PAG synaptosomes were obtained to determine the presence of CaMKII P-Thr286, NR1 C1 P-Ser890, P-Ser897, and NR2A P-Tyr 1325. The assay was repeated at least twice. The data from the S1RA-morphine intervals that failed to enhance analgesia but conferred protection from tolerance are framed. *For every postopioid interval, the symbol indicates that S1RA produced a significant difference from the group receiving only morphine, ANOVA-Student–Newman–Keuls test,p<0.05. The details are shown in Figure 5.(B) Protection against morphine acute antinociceptive tolerance. A priming icv dose of 10 nmol morphine reduced the analgesic response to a second and identical test dose of the opioid when administered 24 h later. Increasing doses of S1RA, BD1047, and BD1063 were icv-injected at 30 min before the morphine priming dose, and the analgesic effect of the test dose was evaluated 24 h later. Analgesia was measured in the thermal tail-flick test at the peak effect for morphine analgesia, 30 min postopioid treatment. Effect of the interval between S1RA and the morphine priming dose on acute tolerance. The σ1R antagonist S1RA was administered icv at 10, 30 min, 1, or 24 h before the morphine priming dose (10 nmol), and the analgesic effects of identical doses were evaluated 24 h (test dose 1) and 48 h (test dose 2) later. Each bar indicates the mean±SEM of the analgesia;n=6 mice. *Significantly different from the group that received saline instead of the σ1R ligand before morphine priming dose,p<0.05.(C) Mice were administered morphine daily for 6 days (10 nmol, icv), and antinociception was evaluated by the tail flick test 30 min after injection. On day 7, the administration of S1RA (3 nmol) to morphine tolerant mice restored the antinociceptive effect of the opioid. Each point/bar represents the mean±SEM of the data from 10 mice. *Significantly different from the group that received the first dose of morphine (day 0),p<0.05. Immunodetection of NMDAR-related signals in the PAG of mice not exposed to morphine (control), mice that received morphine for 7 days and mice that after 6 days of morphine treatment received 3 nmol S1RA plus 10 nmol morphine on day 7. *Significantly different from the control group that received saline instead of morphine,p<0.05. Details as in Figure 5C.
The redox-regulated coupling of NMDARs with MORs: effect of σ1R ligands. (A) MOR-mediated activation of NMDARs:(I) Zinc-mediated association of PKCγ with the HINT1 protein. Zinc was removed from the recombinant proteins (TPEN-EDTA buffer) before incubation of 200 nM HINT1 with 100 nM GST-PKCγ in presence of ZnCl2. GST alone did not bind to the HINT1 protein. CRD stands for cysteine-rich domain and P for precipitation of the GST protein with GS. A similar study was conducted between 100 nM GST-RGSZ2 and HINT1.(II) The RGSZ2, PKCγ, and HINT1 form a ternary complex: 200 nM HINT1 were incubated with 100 nM GST-RGSZ2 in the presence of 100 nM ZnCl2 and increasing concentrations of PKCγ. Details as in(I).(III) PKCγ disrupts HINT1-RGSZ2 association in presence of GαGTPγS subunits. GST-RGSZ2 (100 nM) and HINT1 (200 nM) were incubated in the absence or presence of 100 nM Gαi2GTPγS and of PKCγ.(IV) Effect of PKCγ on RGSZ2 and HINT1. RGSZ2 (100 nM) or HINT1 (100 nM) were incubated for 20 min at RT with 30 nM PKCγ. The PKCγ-induced phosphorylation of RGSZ2 and HINT1 was evaluated using specific anti-phospho antibodies.(V) Effect of HINT1 phosphorylation on its association with RGSZ2 and the C-terminal cytosolic region of NR1 subunit (C0-C1-C2). Native and PKC-phosphorylated HINT1 proteins (200 nM) were incubated with either 100 nM GST-RGSZ2 or GST-NR1.(VI) Phosphorylation of NR1 C0-C1-C2 by PKC, and(VII) its association with HINT1 and σ1R. Further details in Materials and Methods section.(B)Left: Effect of PG and PN sulfate on the association σ1R-NR1 C0-C1-C2. Agarose-NR1 was preincubated in the presence of 2.5 mM CaCl2 (30 min, RT) with the σ1R (100 nM) before the addition of 30 μM PG or PN (30 min, RT). P indicates that agarose was recovered and washed before the analysis of the NR1-bound σ1R through SDS-PAGE and WB. Each bar represents the mean±SEM of three determinations using different gels and blots. *Significant differences with respect the control without neurosteroid, ANOVA-Student–Newman–Keuls test;p<0.05.Right: Influence of increasing concentrations of PG on the association of NR1 with σ1Rs. Agarose-NR1 was incubated with the σ1R before the addition of PG. Agarose-NR1 carrying the associated σ1Rs was recovered and washed before the addition of 200 nM HINT1 or 100 nM CaM (in the presence of 2.5 mM CaCl2 and of 30 μM peptide 4).Low: This assay was also conducted with σ1R antagonists (S1RA and BD1047) and the agonist PRE084 in the absence or presence of CaM.Diagram: S1RA removes the σ1R from the NR1 subunit, favoring the binding of Ca2+-CaM, which impairs the interaction of NMDARs with MOR-HINT1 complexes. As a result, morphine only recruits a fraction of the NMDAR activity that is required to control its effects. Amino acid charge, see key in Fig. 3C. GS, glutathione-sepharose; WB, Western blotting. To see this illustration in color, the reader is referred to the web version of this article atwww.liebertpub.com/ars
The MOR-NMDAR cross-regulation requires NO and zinc metabolism: the role of σ1Rs. (A) Because σ1R−/− mice display enhanced antinociception to opioids, the effect of the direct activation of NMDARs by icv-injection of NMDA and of NOS inhibition, 3 nmol morphine was studied instead of 10 nmol used in wild-type mice. Saline or 50 pmol NMDA, 7 nmol L-NNA were icv-injected at 20 min before morphine treatment into wild-type and σ1R−/− mice, and analgesia was determined using in the warm water tail-flick test. *Significantly different from the group that received saline and morphine, ANOVA-Student–Newman–Keuls test,p<0.05.(B) NOS provides the zinc ions that are required for the recruitment of PKCγ to the HINT1 protein in the MOR environment. PAG synaptosomes obtained from wild-type mice with and withoutin vivo inhibition of NOS, σ1R−/− mice, and HINT1−/− mice were incubated for 4 h at 4°C with ZnCl2, the NO generator SNAP, and the metal ion chelator TPEN. Subsequently, free zinc ions were removed by centrifugation and extensive washing. The synaptosomal membranes were then solubilized and incubated with affinity-purified IgGs raised against extracellular sequences in MOR. The MOR-associated proteins were then separated by SDS-PAGE and analyzed by Western blotting. Doses of reactives and the incubation time were taken from Refs. (51, 54). IP signifies immunoprecipitation and WB analysis.(C) Rescue of morphine acute analgesic tolerancevia inhibition of NMDAR, NOS, or PKC. A morphine priming dose of 10 nmol was icv-injected, and analgesia was evaluated 30 min later in the “tail-flick” test. The noncompetitive NMDAR antagonist MK801 (1 nmol), the NOS inhibitors L-NNA (7 nmol) and L-NAME (20 nmol), or the PKC inhibitor Gö7874 (1 nmol) were icv-injected at 30 min before administering 24 h later an identical morphine test dose of 10 nmol, and analgesia was again measured 30 min later. Each bar indicates the mean±SEM of the analgesia;n=8 mice. *Significantly different from the group that received saline before the morphine test dose,p<0.05. Recovery from morphine acute antinociceptive tolerance produced by a single dose of 10 nmol morphine in wild-type and σ1R−/− mice: effect of the antagonist of σ1Rs, S1RA. After icv-injecting all of the mice with the morphine priming dose of 10 nmol, the analgesia was evaluated in the thermal tail-flick 30 min later. At the time intervals that are indicated in the figure, a different group of four mice received a test dose of 10 nmol morphine, and analgesia was subsequently evaluated 30 min later. *Significantly different from the control group that received the priming dose of morphine, ANOVA, Student–Newman–Keuls test,p<0.05. In a parallel assay, the mice received 1 nmol S1RA at 30 min before the morphine priming dose. The evaluation of antinociceptive tolerance was as described earlier. *Significantly different from the control group that received S1RA and the priming dose of morphine,p<0.05. NO, nitric oxide.
The σ1R connects MOR with the negative regulation of NMDAR. (A) Presence of NR1 subunits, HINT1 and σ1R in the synaptosomes of PAG obtained from wild-type and σ1R−/− mice. IP: MOR or NR1 was immunoprecipitated, and the co-precipitated proteins were detected by WB. *Significantly different from the paired group (n=3), ANOVA, Student-Newman–Keuls test,p<0.05. WT (wild-type mice), KO (σ1R−/− mice), and P2 (synaptosomal fraction).(B) Morphine promotes little activation of the NMDAR-CaMKII pathway in σ1R−/− mice. Mice were icv-injected with 10 nmol morphine, andex vivo determinations were performed at the indicated postopioid time intervals. In σ1R−/− mice, MOR binding to NR1 subunits was impaired, and then morphine hardly altered the association that remained. Moreover, in the absence of σ1Rs, morphine recruited little CaMKII activity and only for a short interval. Details in Figure 5C and Supplementary Figure S4.(C) The icv-injection of the recombinant σ1R in σ1R−/− mice reduced the antinociceptive potency of morphine. The mice were icv-injected with 0.5 nmol recombinant σ1R, and the effect of morphine was evaluated 24 h later. *Significantly different from the group that received saline instead of the σ1R,p<0.05. The icv-injection of the σ1R restored the NMDAR negative regulation on MORs. The σ1R−/− mice that had received the σ1R were icv-injected with 50 pmol NMDA and 10 nmol morphine 24 h later. *Significantly different from the group that received saline instead of NMDA,p<0.05.Inset: Solubilized brain membranes from σ1R−/− mice were incubated with biotinylated IgGs directed against the NR1. After recovery with streptavidin-sepharose (P), the NR1-containing complexes were exposed to σ1R recombinant protein (200 nM) before detecting HINT1-associated proteins by SDS-PAGE chromatography and WB. This study was repeated at least twice using different preparations. Equal loading was determined from the NR1 signal.
The σ1R antagonist S1RA transfers HINT1 proteins from morphine-activated MORs to NMDAR NR1 subunits. (A) Groups of 48 mice each received an icv injection of only morphine or 3 nmol S1RA at 10, 30 min, 1, 3, or 24 h before treatment with 10 nmol morphine. A total of eight mice from each group were sacrificed at 90 min, 6 or 24 h after opioid treatment. Control mice received saline instead of S1RA or morphine. The MORs were IP from PAG synaptosomes, and the co-precipitated NR1 subunits were immunodetected by WB. *Significantly different from the respective control group that received saline instead of morphine,p<0.05. Association of HINT1 with MORs and NR1 subunits. In the experimental groups described earlier, the association of HINT1 proteins with MORs and NR1 subunits was determined for control, morphine- and S1RA-morphine-treated groups at 90 min and 24 h postmorphine treatment. Thecircle shows that morphine alone induces the transfer of HINT1 to NR1 subunits. The S1RA-morphine intervals that did not enhance analgesia but conferred protection from tolerance are framed. Controls of MOR and NR1 immunoprecipitation are shown in Supplementary Figure S7. The diagrams represent the framed S1RA-morphine intervals. S1RA administered 1 or 24 h before morphine did not enhance analgesia or alter the MOR-promoted NMDAR activity at 24 h, as indicated by NMDAR (****) (Figs. 5A and 6A). However, some protection against analgesic tolerance was observed (Fig. 6B). On the S1RA-mediated removal of σ1Rs, the NR1 subunit binds tightly to HINT1 at the MOR C terminus. HINT1 carries the activated PKCγ that acts on NR1 C1 S890/896, promoting the separation of the MOR C terminus from NR1-HINT1. Under these circumstances, CaMKII and PKC barely reach the MOR, and then analgesic tolerance to morphine develops at a slower rate (6, 9, 48).(B) Native or mutated NR1 T879A (100 nM) binds similarly to HINT1 (200 nM). While PKC-phosphorylated native NR1 displayed poor affinity for HINT1, PKC-phosphorylated NR1 T879A bound to the HINT1 protein. The phosphorylation of either form of NR1 greatly augmented its association with σ1Rs. Amino acid charge, see key in Fig. 3C. To see this illustration in color, the reader is referred to the web version of this article atwww.liebertpub.com/ars
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