iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1007/s00424-014-1452-z
Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy | Pflügers Archiv - European Journal of Physiology Skip to main content

Advertisement

Springer Nature Link
Log in

Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of insufficient knowledge about the mechanisms for this hypersensitization, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs having significant side effects or potential for abuse. Recent studies have established that the CaV3.2 isoform of T-channels makes a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that the glycosylation inhibitor neuraminidase can inhibit the native and recombinant CaV3.2 T-currents in vitro and completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity via glycosylation may facilitate development of novel therapies for treatment of painful PDN. Pharmacological targeting the specific pathogenic mechanism rather than the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Calcutt NA (2013) Location, location, location? Is the pain of diabetic neuropathy generated by hyperactive sensory neurons? Diabetes 62:3658–3660

    Article  CAS  PubMed  Google Scholar 

  2. Cao XH, Byun HS, Chen SR, Pan HL (2011) Diabetic neuropathy enhances voltage-activated Ca2+ channel activity and its control by M4 muscarinic receptors in primary sensory neurons. J Neurochem 119(3):594–603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Carbone E, Lux HD (1984) A low-voltage activated, fully inactivating Ca2+ channel in vertebrate sensory neurons. Nature 310:501–502

    Article  CAS  PubMed  Google Scholar 

  4. Centers for Disease Control and Prevention (2011) National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. 2011 ed, Atlanta, GA: US Department of Health and Human Services, Center for Disease Control and Prevention. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

  5. Cohen DM (2006) Regulation of TRP channels by N-linked glycosylation. Semin Cell Dev Biol 17(6):630–637

    Article  CAS  PubMed  Google Scholar 

  6. Dubreuil AS, Boukhaddaoui H, Desmadryl G, Martinez-Salgado C, Moshourab R, Lewin GR, Carroll P, Valmier J, Scamps F (2004) Role of T-type calcium current in identified d-hair mechanoreceptor neurons studied in vitro. J Neurosci 24:8480–8484

    Article  CAS  PubMed  Google Scholar 

  7. Edwards JL, Vincent AM, Cheng HT, Feldman EL (2008) Diabetic neuropathy: mechanisms to management. Pharmacol Ther 120:1–34

    Article  CAS  PubMed  Google Scholar 

  8. Gooch C, Podwall D (2004) The diabetic neuropathies. Neurologist 10:311–322

    Article  PubMed  Google Scholar 

  9. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA (2003) The health care cost of diabetic peripheral neuropathy in the US. Diabetes Care 26(6):1790–1795

    Article  PubMed  Google Scholar 

  10. Hall KE, Sima AA, Wiley JW (1995) Voltage-dependent calcium currents are enhanced in dorsal root ganglion neurones from the Bio Bred/Worchester diabetic rat. J Physiol (London) 486(Pt 2):313–322

    CAS  Google Scholar 

  11. Hong S, Wiley JW (2005) Early painful diabetic neuropathy is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 280(1):618–627

    CAS  PubMed  Google Scholar 

  12. Jack M, Wright D (2012) Role of advanced glycation end products and glyoxalase I in diabetic peripheral sensory neuropathy. Transl Res 159(5):355–365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Jacus MO, Uebele VN, Renger JJ, Todorovic SM (2012) Presynaptic CaV3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons. J Neurosci 32(27):9374–9382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM (2007) Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 27(12):3305–3316

    Article  CAS  PubMed  Google Scholar 

  15. Khomula EV, Viatchenko-Karpinski VY, Borisyuk AL, Duzhyy DE, Belan PV, Voitenko NV (2013) Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy. Biochim Biophys Acta 1832(5):636–649

    Article  CAS  PubMed  Google Scholar 

  16. Latham JR, Pathirathna S, Jagodic MM, Choe WJ, Levin ME, Nelson MT, Lee WY, Krishnan K, Covey D, Todorovic SM, Jevtovic-Todorovic V (2009) Selective T-type calcium channel blockade alleviates hyperalgesia in ob/ob mice. Diabetes 58(11):2656–2665

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, Orestes P, Latham JR, Todorovic SM, Jevtovic-Todorovic V (2009) In vivo silencing of the Cav3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain 145(1–2):184–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Moremen KW, Tiemeyer M, Naim AV (2012) Vertebrate protein glycosylation: diversity, synthesis, and function. Nat Rev 13:448–462

    Article  CAS  Google Scholar 

  19. Nelson MT, Joksovic PM, Perez-Reyes E, Todorovic SM (2005) The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. J Neurosci 25:8766–8775

    Article  CAS  PubMed  Google Scholar 

  20. Nelson MT, Woo J, Kang H-W, Barrett PQ, Vitko J, Perez-Reyes E, Lee J-H, Shin H-S, Todorovic SM (2007) Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels. J Neurosci 27(31):8250–8260

    Article  CAS  PubMed  Google Scholar 

  21. Obrosova IG (2009) Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 6(4):638–647

    Article  CAS  PubMed  Google Scholar 

  22. Orestes P, Osuru HP, McIntire WE, Jacus MO, Salajegheh R, Jagodic MM, Choe W, Lee J, Lee SS, Rose KE, Poiro N, Digruccio MR, Krishnan K, Covey DF, Lee JH, Barrett PQ, Jevtovic-Todorovic V, Todorovic SM (2013) Reversal of neuropathic pain by targeting glycosylation of CaV3.2 T-type calcium channels. Diabetes 62:3828–3838

    Article  CAS  PubMed  Google Scholar 

  23. Pabbidi RM, Cao DS, Parihar A, Pauza ME, Premkumar LS (2008) Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons. Mol Pharmacol 73(3):995–1004

    Article  CAS  PubMed  Google Scholar 

  24. Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS (2008) Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 1(4):9

    Article  Google Scholar 

  25. Pertusa M, Madrid R, Morenilla-Palao C, Belmonte C, Viana F (2012) N-glycosylation of TRPM8 ion channels modulates temperature sensitivity of cold thermoreceptor neurons. J Biol Chem 287(22):18218–18229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Shankarappa SA, Piedras-Rentería ES, Stubbs EB Jr (2011) Forced-exercise delays neuropathic pain in experimental diabetes: effects on voltage-activated calcium channels. J Neurochem 118(2):224–236

    Article  CAS  PubMed  Google Scholar 

  27. Shin JB, Martinez-Salgado C, Heppenstall PA, Lewin GR (2003) A T-type calcium channel required for normal function of a mammalian mechanoreceptor. Nat Neurosci 6(7):724–730

    Article  CAS  PubMed  Google Scholar 

  28. Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895–1911

    CAS  PubMed  Google Scholar 

  29. Todorovic SM, Jevtovic-Todorovic V (2011) T-type voltage-gated calcium channels as targets for development of novel pain therapies. Br J Pharmacol 163(3):484–495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Veves A, Backonja M, Malik RA (2007) Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med 9:660–674

    Article  Google Scholar 

  31. Weis N, Black SAG, Bladen C, Chen L, Zamponi GW (2013) Surface expression and function of CaV3.2 T-type calcium channels are controlled by asparagines-linked glycosylation. Pflugers Arch-Euro J Physiol 465(8):1159–1170

    Article  Google Scholar 

  32. White G, Lovinger DM, Weight FF (1989) Transient low-threshold Ca2+ current triggers burst firing through an afterdepolarizing potential in an adult mammalian neuron. PNAS USA 86:6802–6806

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152(3 Suppl):S2–S15

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Our research is supported by the American Diabetes Association National Award for Basic Research 7-09-BS-190 (to S.M.T.), Dr. Harold Carron Endowment fund (to V.J-T.), and research funds from the Department of Anesthesiology at the University of Virginia, Charlottesville, VA, USA.

Author information

Authors and Affiliations

  1. Departments of Anesthesiology and Neuroscience, University of Virginia School of Medicine, Mail Box 800710, Charlottesville, VA, 22908-0710, USA

    Slobodan M. Todorovic & Vesna Jevtovic-Todorovic

Authors
  1. Slobodan M. Todorovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vesna Jevtovic-Todorovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Slobodan M. Todorovic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Todorovic, S.M., Jevtovic-Todorovic, V. Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy. Pflugers Arch - Eur J Physiol 466, 701–706 (2014). https://doi.org/10.1007/s00424-014-1452-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1452-z

Keywords

Search

Navigation