egl-4 modulates electroconvulsive seizure duration in C. elegans

  • Monica G. Risley
  • Stephanie P. Kelly
  • Justin Minnerly
  • Kailiang Jia
  • Ken Dawson-Scully
Original Article
  • 38 Downloads

Abstract

Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.

Keywords

C. elegans Seizure Epilepsy Protein kinase G PKG Electroconvulsive seizure 

Notes

Acknowledgements

Research was supported by a compound transfer grant (CTP) Grant from Pfizer WI225058 for KD-S. Some strains were provided by the CGC, which is funded by National Institute of Health (NIH) Office of Research Infrastructure Programs (P40 OD010440).

Funding

Research was supported by a compound transfer grant (CTP) grant from Pfizer WI225058 for KD-S.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Barrese V, Miceli F, Soldovieri MV, Ambrosino P, Iannotti FA, Cilio MR et al (2010) Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin Pharmacol 2:225–236.  https://doi.org/10.2147/cpaa.s15369 PubMedPubMedCentralGoogle Scholar
  2. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P (2012) Patterns of treatment response in newly diagnosed epilepsy. Neurology 78(20):1548–1554.  https://doi.org/10.1212/WNL.0b013e3182563b19 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Calahorro F, Ruiz-Rubio M (2011) Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson’s disease, Alzheimer’s disease and autism spectrum disorder. Invert Neurosci 11(2):73–83.  https://doi.org/10.1007/s10158-011-0126-1 CrossRefPubMedGoogle Scholar
  4. Caplan SL, Milton SL, Dawson-Scully K (2013) A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction. J Neurophysiol 109(3):649–658.  https://doi.org/10.1152/jn.00784.2011 CrossRefPubMedGoogle Scholar
  5. Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC (1994) Green fluorescent protein as a marker for gene expression. Science 263(5148):802–805CrossRefPubMedGoogle Scholar
  6. Daniels SA, Ailion M, Thomas JH, Sengupta P (2000) egl-4 acts through a transforming growth factor-beta/SMAD pathway in Caenorhabditis elegans to regulate multiple neuronal circuits in response to sensory cues. Genetics 156(1):123–141PubMedPubMedCentralGoogle Scholar
  7. Dawson-Scully K, Bukvic D, Chakaborty-Chatterjee M, Ferreira R, Milton SL, Sokolowski MB (2010) Controlling anoxic tolerance in adult Drosophila via the cGMP–PKG pathway. J Exp Biol 213(Pt 14):2410–2416.  https://doi.org/10.1242/jeb.041319 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Friedman LK, Slomko AM, Wongvravit JP, Naseer Z, Hu S, Wan WY et al (2015) Efficacy of retigabine on acute limbic seizures in adult rats. J Epilepsy Res 5(2):46–59.  https://doi.org/10.14581/jer.15010 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fujiwara M, Sengupta P, McIntire SL (2002) Regulation of body size and behavioral state of C. elegans by sensory perception and the EGL-4 cGMP-dependent protein kinase. Neuron 36(6):1091–1102CrossRefPubMedGoogle Scholar
  10. Guerrini R, Rosati A, Giordano F, Genitori L, Barba C (2013) The medical and surgical treatment of tumoral seizures: current and future perspectives. Epilepsia 54(Suppl 9):84–90.  https://doi.org/10.1111/epi.12450 CrossRefPubMedGoogle Scholar
  11. Hahm JH, Kim S, Paik YK (2009) Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegans. Aging Cell 8(4):473–483.  https://doi.org/10.1111/j.1474-9726.2009.00495.x CrossRefPubMedGoogle Scholar
  12. Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, Caldwell GA (2008) Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson’s disease model. Proc Natl Acad Sci USA 105(2):728–733.  https://doi.org/10.1073/pnas.0711018105 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kaun KR, Hendel T, Gerber B, Sokolowski MB (2007) Natural variation in Drosophila larval reward learning and memory due to a cGMP-dependent protein kinase. Learn Mem 14(5):342–349.  https://doi.org/10.1101/lm.505807 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Kim JB (2014) Channelopathies. Korean J Pediatr 57(1):1–18.  https://doi.org/10.3345/kjp.2014.57.1.1 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Krzyzanowski MC, Brueggemann C, Ezak MJ, Wood JF, Michaels KL, Jackson CA et al (2013) The C. elegans cGMP-dependent protein kinase EGL-4 regulates nociceptive behavioral sensitivity. PLoS Genet 9(7):e1003619.  https://doi.org/10.1371/journal.pgen.1003619 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Lee SK (2014) Old versus new: why do we need new antiepileptic drugs? J Epilepsy Res 4(2):39–44CrossRefPubMedPubMedCentralGoogle Scholar
  17. L’Etoile ND, Coburn CM, Eastham J, Kistler A, Gallegos G, Bargmann CI (2002) The cyclic GMP-dependent protein kinase EGL-4 regulates olfactory adaptation in C. elegans. Neuron 36(6):1079–1089CrossRefPubMedGoogle Scholar
  18. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH et al (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 93(25):14940–14944CrossRefPubMedPubMedCentralGoogle Scholar
  19. Link CD, Taft A, Kapulkin V, Duke K, Kim S, Fei Q et al (2003) Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer’s disease model. Neurobiol Aging 24(3):397–413CrossRefPubMedGoogle Scholar
  20. Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H et al (2010) C. elegans phototransduction requires a G protein-dependent cGMP pathway and a taste receptor homolog. Nat Neurosci 13(6):715–722.  https://doi.org/10.1038/nn.2540 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Loscher W, Schmidt D (2011) Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 52(4):657–678.  https://doi.org/10.1111/j.1528-1167.2011.03024.x CrossRefPubMedGoogle Scholar
  22. Mary Jane E, Catharyn TL, Andrea MS, Larisa MS (2012) Epilepsy across the spectrum: promoting health and understanding. The National Academies Press, Washington, DCGoogle Scholar
  23. Mery F, Belay AT, So AK, Sokolowski MB, Kawecki TJ (2007) Natural polymorphism affecting learning and memory in Drosophila. Proc Natl Acad Sci USA 104(32):13051–13055.  https://doi.org/10.1073/pnas.0702923104 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Opperman KJ, Mulcahy B, Giles AC, Risley MG, Birnbaum RL, Tulgren ED et al (2017) The HECT family ubiquitin ligase EEL-1 regulates neuronal function and development. Cell Rep 19(4):822–835.  https://doi.org/10.1016/j.celrep.2017.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Raizen DM, Cullison KM, Pack AI, Sundaram MV (2006) A novel gain-of-function mutant of the cyclic GMP-dependent protein kinase egl-4 affects multiple physiological processes in Caenorhabditis elegans. Genetics 173(1):177–187.  https://doi.org/10.1534/genetics.106.057380 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Renger JJ, Yao WD, Sokolowski MB, Wu CF (1999) Neuronal polymorphism among natural alleles of a cGMP-dependent kinase gene, foraging, in Drosophila. J Neurosci 19(19):RC28CrossRefPubMedGoogle Scholar
  27. Risley MG, Kelly SP, Jia K, Grill B, Dawson-Scully K (2016) Modulating behavior in C. elegans using electroshock and antiepileptic drugs. PLoS ONE 11(9):e0163786.  https://doi.org/10.1371/journal.pone.0163786 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Rundfeldt C (1997) The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur J Pharmacol 336(2–3):243–249CrossRefPubMedGoogle Scholar
  29. Saeki S, Yamamoto M, Iino Y (2001) Plasticity of chemotaxis revealed by paired presentation of a chemoattractant and starvation in the nematode Caenorhabditis elegans. J Exp Biol 204(Pt 10):1757–1764PubMedGoogle Scholar
  30. Szaflarski JP, Nazzal Y, Dreer LE (2014) Post-traumatic epilepsy: current and emerging treatment options. Neuropsychiatr Dis Treat 10:1469–1477.  https://doi.org/10.2147/ndt.s50421 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Timmons L, Court DL, Fire A (2001) Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans. Gene 263(1–2):103–112CrossRefPubMedGoogle Scholar
  32. White JG, Southgate E, Thomson JN, Brenner S (1986) The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 314(1165):1–340CrossRefPubMedGoogle Scholar
  33. Zhang Y, Lu H, Bargmann CI (2005) Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438(7065):179–184.  https://doi.org/10.1038/nature04216 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Monica G. Risley
    • 1
    • 2
  • Stephanie P. Kelly
    • 1
    • 2
  • Justin Minnerly
    • 1
    • 2
  • Kailiang Jia
    • 1
    • 2
  • Ken Dawson-Scully
    • 1
    • 2
  1. 1.Department of Biological SciencesFlorida Atlantic UniversityBoca RatonUSA
  2. 2.International Max-Planck Research School (IMPRS) for Brain and BehaviorBoca RatonUSA

Personalised recommendations