Skip to main content

Advertisement

SpringerLink
Log in

The Agonist of Adenosine A1 Receptor Induced Desensitization of delta Opioid receptor-mediated Raf-1/MEK/ERK Signaling by Feedback Phosphorylation of Raf-1-Ser289/296/301

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Our previous study found that activation of adenosine A1 receptor (A1R) induced phosphorylation of delta opioid receptor (DOR) and desensitization of its downstream signaling molecules, cAMP and Akt. To further investigate the effect of A1R agonist on DOR signaling and the underlying mechanism, we examined the effect of A1R activation upon binding of its agonist N6-cyclohexyl-adenosine (CHA) on DOR-mediated Raf-1/MEK/ERK activation, and found that prolonged CHA exposure resulted in downregulation of DOR-mediated Raf-1/MEK/ERK signaling pathway. CHA-treatment time dependently attenuated Raf-1-Ser338 phosphorylation induced by [D-Pen2,5] enkephalin (DPDPE), a specific agonist of DOR, and further caused downregulation of the Raf-1/MEK/ERK signaling pathway activated by DOR agonist. Moreover, CHA exposure time-dependently induced the phosphorylation of Raf-1-Ser289/296/301, the inhibitory phosphorylation sites that were regulated by negative feedback, thereby inhibiting activation of the MEK/ERK pathway, and this effect could be blocked by MEK inhibitor U0126. Finally, we proved that the heterologous desensitization of the Raf-1/MEK/ERK cascade was essential in the regulation of anti-nociceptive effect of DOR agonists by confirming that such effect was inhibited by pretreatment of CHA. Therefore, we conclude that the activation of A1R inhibits DOR-mediated MAPK signaling pathway via heterologous desensitization of the Raf-1/MEK/ERK cascade, which is a result of ERK-mediated Raf-1-Ser289/296/301 phosphorylation mediated by activation of A1R.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

Data sharing not applicable to this article as no datasets were generated or analysed.

during the current study.

References

  1. Araldi D, Ferrari LF, Levine JD (2016) Adenosine-A1 receptor agonist induced hyperalgesic priming type II. Pain 157:698–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. De Lander GE, Keil GJ 2nd (1994) Antinociception induced by intrathecal coadministration of selective adenosine receptor and selective opioid receptor agonists in mice. J Pharmacol Exp Ther 268:943–951

  3. Peart JN, Gross GJ (2003) Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol 285:H81–89

    Article  CAS  PubMed  Google Scholar 

  4. Tosh DK, Ciancetta A, Mannes P, Warnick E, Janowsky A, Eshleman AJ, Gizewski E, Brust TF, Bohn LM, Auchampach JA, Gao ZG, Jacobson KA (2018) Repurposing of a Nucleoside Scaffold from Adenosine receptor agonists to opioid receptor antagonists. ACS Omega 3:12658–12678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cheng Y, Tao YM, Sun JF, Wang YH, Xu XJ, Chen J, Chi ZQ, Liu JG (2010) Adenosine A(1) receptor agonist N(6)-cyclohexyl-adenosine induced phosphorylation of delta opioid receptor and desensitization of its signaling. Acta Pharmacol Sin 31:784–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shaw S, Uniyal A, Gadepalli A, Tiwari V, Belinskaia DA, Shestakova NN, Venugopala KN, Deb PK, Tiwari V (2020) Adenosine receptor signalling: probing the potential pathways for the ministration of neuropathic pain. Eur J Pharmacol 889:173619

    Article  CAS  PubMed  Google Scholar 

  7. Diao XT, Yao L, Ma JJ, Zhang TY, Bai HH, Suo ZW, Yang X, Hu XD (2020) Analgesic action of adenosine A1 receptor involves the dephosphorylation of glycine receptor alpha1(ins) subunit in spinal dorsal horn of mice. Neuropharmacology 176:108219

    Article  CAS  PubMed  Google Scholar 

  8. Chang JK, Cornwell WD, Rogers TJ (2021) The mu-opioid receptor induces miR-21 expression and is ERK/PKCmu-dependent. J Neuroimmunol 356:577585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Little AS, Smith PD, Cook SJ (2013) Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene 32:1207–1215

    Article  CAS  PubMed  Google Scholar 

  10. Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885

    Article  CAS  PubMed  Google Scholar 

  11. Jaffre F, Miller CL, Schanzer A, Evans T, Roberts AE, Hahn A, Kontaridis MI (2019) Inducible pluripotent stem cell-derived cardiomyocytes reveal aberrant Extracellular regulated kinase 5 and mitogen-activated protein kinase kinase 1/2 signaling concomitantly promote hypertrophic cardiomyopathy in RAF1-Associated Noonan Syndrome. Circulation 140:207–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Takahashi M, Li Y, Dillon TJ, Kariya Y, Stork PJS (2017) Phosphorylation of the C-Raf N region promotes Raf Dimerization.Mol Cell Biol37

  13. Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK (2003) Protein phosphatase 2A positively regulates ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13:1356–1364

    Article  CAS  PubMed  Google Scholar 

  14. Dumaz N, Marais R (2003) Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with ras. J Biol Chem 278:29819–29823

    Article  CAS  PubMed  Google Scholar 

  15. Han S, Meier KE (2009) Integrated modulation of phorbol ester-induced raf activation in EL4 lymphoma cells. Cell Signal 21:793–800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Balan V, Leicht DT, Zhu J, Balan K, Kaplun A, Singh-Gupta V, Qin J, Ruan H, Comb MJ, Tzivion G (2006) Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase. Mol Biol Cell 17:1141–1153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell 17:215–224

    Article  CAS  PubMed  Google Scholar 

  18. Yang PP, Yeh GC, Yeh TK, Xi J, Loh HH, Law PY, Tao PL (2016) Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. Pharmacol Res 111:867–876

    Article  CAS  PubMed  Google Scholar 

  19. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    Article  CAS  PubMed  Google Scholar 

  20. Cahill CM, Holdridge SV, Liu SS, Xue L, Magnussen C, Ong E, Grenier P, Sutherland A, Olmstead MC (2022) Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain. J Neurosci Res 100:129–148

    Article  CAS  PubMed  Google Scholar 

  21. Zhang X, Kim KM (2017) Multifactorial regulation of G protein-coupled receptor endocytosis. Biomol Ther (Seoul) 25:26–43

    Article  PubMed  Google Scholar 

  22. Xu C, Hong MH, Zhang LS, Hou YY, Wang YH, Wang FF, Chen YJ, Xu XJ, Chen J, Xie X, Ma L, Chi ZQ, Liu JG (2010) Serine 363 of the {delta}-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands. J Cell Sci 123:4259–4270

    Article  CAS  PubMed  Google Scholar 

  23. Tran NH, Wu X, Frost JA (2005) B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem 280:16244–16253

    Article  CAS  PubMed  Google Scholar 

  24. Xu C, Zhang Y, Zheng H, Loh HH, Law PY (2014) Morphine modulates mouse hippocampal progenitor cell lineages by upregulating miR-181a level. Stem Cells 32:2961–2972

    Article  CAS  PubMed  Google Scholar 

  25. Xu C, Zheng H, Loh HH, Law PY (2015) Morphine promotes astrocyte-preferential differentiation of mouse hippocampal progenitor cells via PKCepsilon-Dependent ERK activation and TRBP phosphorylation. Stem Cells 33:2762–2772

    Article  CAS  PubMed  Google Scholar 

  26. Navratilova E, Waite S, Stropova D, Eaton MC, Alves ID, Hruby VJ, Roeske WR, Yamamura HI, Varga EV (2007) Quantitative evaluation of human delta opioid receptor desensitization using the operational model of drug action. Mol Pharmacol 71:1416–1426

    Article  CAS  PubMed  Google Scholar 

  27. Leduc-Pessah H, Xu C, Fan CY, Dalgarno R, Kohro Y, Sparanese S, Burke NN, Jacobson KA, Altier C, Salvemini D, Trang T (2021) Spinal A3 adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats. J Neurosci Res

  28. Okumura T, Nozu T, Ishioh M, Igarashi S, Kumei S, Ohhira M (2020) Adenosine A1 receptor agonist induces visceral antinociception via 5-HT1A, 5-HT2A, dopamine D1 or cannabinoid CB1 receptors, and the opioid system in the central nervous system. Physiol Behav 220:112881

    Article  CAS  PubMed  Google Scholar 

  29. Ramos-Zepeda GA, Herrero-Zorita C, Herrero JF (2014) Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine and kappa-opioid receptors in rat spinal cord nociceptive reflexes. Behav Pharmacol 25:741–749

    Article  CAS  PubMed  Google Scholar 

  30. Quirion B, Bergeron F, Blais V, Gendron L (2020) The Delta-Opioid receptor; a target for the treatment of Pain. Front Mol Neurosci 13:52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berthiaume S, Abdallah K, Blais V, Gendron L (2020) Alleviating pain with delta opioid receptor agonists: evidence from experimental models. J Neural Transm (Vienna) 127:661–672

    Article  PubMed  Google Scholar 

  32. Kibaly C, Xu C, Cahill CM, Evans CJ, Law PY (2019) Non-nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect. Nat Rev Neurosci 20:5–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Persson AI, Thorlin T, Bull C, Zarnegar P, Ekman R, Terenius L, Eriksson PS (2003) Mu- and delta-opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors. Eur J Neurosci 17:1159–1172

    Article  PubMed  Google Scholar 

  34. Lutz PE, Kieffer BL (2013) Opioid receptors: distinct roles in mood disorders. Trends Neurosci 36:195–206

    Article  CAS  PubMed  Google Scholar 

  35. Torregrossa MM, Isgor C, Folk JE, Rice KC, Watson SJ, Woods JH (2004) The delta-opioid receptor agonist (+)BW373U86 regulates BDNF mRNA expression in rats. Neuropsychopharmacology 29:649–659

    Article  CAS  PubMed  Google Scholar 

  36. Liu YJ, Chen J, Li X, Zhou X, Hu YM, Chu SF, Peng Y, Chen NH (2019) Research progress on adenosine in central nervous system diseases. CNS Neurosci Ther 25:899–910

    Article  PubMed  PubMed Central  Google Scholar 

  37. Caruana DA, Dudek SM (2020) Adenosine A1 receptor-mediated synaptic depression in the developing hippocampal area CA2. Front Synaptic Neurosci 12:21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Serchov T, Schwarz I, Theiss A, Sun L, Holz A, Dobrossy MD, Schwarz MK, Normann C, Biber K, van Calker D (2020) Enhanced adenosine A1 receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior. Neuropharmacology 162:107834

    Article  CAS  PubMed  Google Scholar 

  39. Li Y, Li L, Wu J, Zhu Z, Feng X, Qin L, Zhu Y, Sun L, Liu Y, Qiu Z, Duan S, Yu YQ (2020) Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors. Elife 9

Download references

Acknowledgements

This work was supported by Zhejiang Provincial Natural Science Foundation of China under Grant. No. LY22H270004, by Zhejiang Chinese Medical University under Grant No. 2020ZG53, and by National Natural Science Foundation of China under Grant No. 82030112. We appreciate the technical support from the Public Platform of Medical Research Center, Academy of Chinese Medical Science, Zhejiang Chinese Medical University.

Author information

Authors and Affiliations

  1. Department of Neurobiology and Acupuncture Research, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Affiliated Hospital of Zhejiang Chinese Medical University, 310053, Hangzhou, China

    Chi Xu & Jing-Gen Liu

  2. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 310053, Hangzhou, China

    Chi Xu & Jing-Gen Liu

  3. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Yun Cheng, Yimin Tao & Jing-Gen Liu

  4. School of Pharmacy, Zhejiang Chinese Medical University, 310053, Hangzhou, China

    Manman Han & Jing-Gen Liu

Authors
  1. Chi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yun Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manman Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yimin Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing-Gen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chi Xu or Jing-Gen Liu.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Chi Xu, Yun Cheng and Manman Han these authors have contributed equally to this work.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, C., Cheng, Y., Han, M. et al. The Agonist of Adenosine A1 Receptor Induced Desensitization of delta Opioid receptor-mediated Raf-1/MEK/ERK Signaling by Feedback Phosphorylation of Raf-1-Ser289/296/301. Neurochem Res 48, 1531–1542 (2023). https://doi.org/10.1007/s11064-022-03843-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-022-03843-2

Keywords

Search

Navigation