egl-4 modulates electroconvulsive seizure duration in C. elegans
- 148 Downloads
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.
KeywordsC. elegans Seizure Epilepsy Protein kinase G PKG Electroconvulsive seizure
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).
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.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
- 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
- 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