Cellular and Molecular Neurobiology

, Volume 30, Issue 4, pp 505–509

The Cdk5 Kinase Downregulates ATP-Gated Ionotropic P2X3 Receptor Function Via Serine Phosphorylation

  • Asha Nair
  • Manuela Simonetti
  • Elsa Fabbretti
  • Andrea Nistri
Short Communication
  • 209 Downloads

Abstract

Cdk5 is an endogenous kinase activated by the neuronal-specific protein p35 and implicated in multiple neuronal functions, including modulation of certain pain responses. We investigated whether Cdk5 could regulate ATP-gated P2X3 receptors that are members of the family of membrane proteins expressed by sensory neurons to transduce nociception in baseline and chronic pain. To study the potential P2X3 receptor modulation by Cdk5, we co-transfected rat P2X3 receptors and Cdk5 into HEK cells and observed increased P2X3 receptor serine phosphorylation together with downregulation of receptor currents only when these genes were transfected together with the gene of the Cdk5 activator p35. The changes in receptor responses were limited to depressed current amplitude as desensitization and recovery were not altered. Transfection of p35 with P2X3 similarly downregulated receptor responses, suggesting that this phenomenon could be observed even with constitutive Cdk5. The present data indicate a novel target to express the action of Cdk5 on membrane proteins involved in pain perception.

Keywords

Purinergic receptors Receptor modulation Patch clamp Serine/threonine kinase p35 HEK cells 

References

  1. Boué-Grabot E, Emerit MB, Toulmé E, Séguéla P, Garret M (2004) Cross-talk and co-trafficking between rho1/GABA receptors and ATP-gated channels. J Biol Chem 279:6967–6975CrossRefPubMedGoogle Scholar
  2. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797CrossRefPubMedGoogle Scholar
  3. Camins A, Verdaguer E, Folch J, Canudas AM, Pallàs M (2006) The role of CdK5/p25 formation/inhibition in neurodegeneration. Drug News Perspect 19:453–460CrossRefPubMedGoogle Scholar
  4. D’Arco M, Giniatullin R, Simonetti M, Fabbro A, Nair A, Nistri A, Fabbretti E (2007) Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J Neurosci 27:8190–8201CrossRefPubMedGoogle Scholar
  5. D’Arco M, Giniatullin R, Leone V, Carloni P, Birsa N, Nair A, Nistri A, Fabbretti E (2009) The C-terminal Src inhibitory kinase (Csk)-mediated tyrosine phosphorylation is a novel molecular mechanism to limit P2X3 receptor function in mouse sensory neurons. J Biol Chem 284:21393–21401CrossRefPubMedGoogle Scholar
  6. Dhavan R, Tsai LH (2001) A decade of CdK5. Nat Rev Mol Cell Biol 2:749–759CrossRefPubMedGoogle Scholar
  7. Giniatullin R, Nistri A, Fabbretti E (2008) Molecular mechanisms of sensitization of pain-transducing P2X3 receptors by the migraine mediators CGRP and NGF. Mol Neurobiol 37:83–90CrossRefPubMedGoogle Scholar
  8. Hellmich MR, Pant HC, Wada E, Battey JF (1992) Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci USA 89:10867–10871CrossRefPubMedGoogle Scholar
  9. Lew J, Winkfein RJ, Paudel HK, Wang JH (1992) Brain praline directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2. J Biol Chem 267:25922–25926PubMedGoogle Scholar
  10. Lew J, Huang OO, Oi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH (1994) A brain-specific acitvator of cyclin-dependent kinase 5. Nature 371:423–426CrossRefPubMedGoogle Scholar
  11. Mager PP, Weber A, Illes P (2004) Bridging the gap between structural bioinformatics and receptor research: the membrane-embedded, ligand-gated, P2X glycoprotein receptor. Curr Top Med Chem 4:1657–1705CrossRefPubMedGoogle Scholar
  12. Pareek TK, Kulkarni AB (2006) Cdk5: a new player in pain signaling. Cell Cycle 5:585–588PubMedGoogle Scholar
  13. Pareek TK, Keller J, Kesavapany S, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB (2006) Cyclin-dependent kinase 5 activity regulates pain signaling. Proc Natl Acad Sci USA 103:791–796CrossRefPubMedGoogle Scholar
  14. Pareek TK, Keller J, Kesavapany S, Agrawal N, Kuner R, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB (2007) Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1. Proc Natl Acad Sci USA 104:660–665CrossRefPubMedGoogle Scholar
  15. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622CrossRefPubMedGoogle Scholar
  16. Sharma P, Steinbach PJ, Sharma M, Amin ND, Barchi JJ Jr, Pant HC (1999) Identification of substrate binding site of cyclin-dependent kinase 5. J Biol Chem 274:9600–9606CrossRefPubMedGoogle Scholar
  17. Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, O’Hare MJ, Callaghan S, Slack RS, Przedborski S, Anisman H, Park DS (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 100:13650–13655CrossRefPubMedGoogle Scholar
  18. Sokolova E, Nistri A, Giniatullin R (2001) Negative cross talk between anionic GABAA and cationic P2X ionotropic receptors of rat dorsal root ganglion neurons. J Neurosci 21:4958–4968PubMedGoogle Scholar
  19. Tang D, Wang JH (1996) Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. Prog Cell Cycle Res 2:205–216PubMedGoogle Scholar
  20. Terada M, Yasuda H, Kogawa S, Maeda K, Haneda M, Hidaka H, Kashiwagi A, Kikkawa R (1998) Expression and activity of cyclin-dependent kinase 5/p35 in adult rat peripheral nervous system. J Neurochem 71:2600–2606PubMedCrossRefGoogle Scholar
  21. Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423CrossRefPubMedGoogle Scholar
  22. Wang Y (2008) The functional regulation of TRPV1 and its role in pain sensitization. Neurochem Res 33:2008–2012CrossRefPubMedGoogle Scholar
  23. Xie WY, He Y, Yang YR, Li YF, Kang K, Xing BM, Wang Y (2009) Disruption of Cdk5-associated phosphorylation of residue threonine-161 of the delta-opioid receptor: impaired receptor function and attenuated morphine antinociceptive tolerance. J Neurosci 29:3551–3564CrossRefPubMedGoogle Scholar
  24. Yang YR, He Y, Zhang Y, Li Y, Li Y, Han Y, Zhu H, Wang Y (2007) Activation of cyclin-dependent kinase 5 (Cdk5) in primary sensory and dorsal horn neurons by peripheral inflammation contributes to heat hyperalgesia. Pain 127:109–120CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Asha Nair
    • 1
  • Manuela Simonetti
    • 1
    • 3
  • Elsa Fabbretti
    • 1
    • 2
  • Andrea Nistri
    • 1
  1. 1.Neurobiology Sector and Italian Institute of Technology UnitInternational School for Advanced Studies (SISSA)TriesteItaly
  2. 2.University of Nova GoricaNova GoricaSlovenia
  3. 3.Pharmacology Institute, Faculty of MedicineUniversity of HeidelbergHeidelbergGermany

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