Myristoyltransferase and calcineurin: Novel molecular therapeutic target for epilepsy Ashakumary Lakshmikuttyamma a,1 , Ponniah Selvakumar a,1 , John Tuchek b , Rajendra K. Sharma a, * a Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan and Health Research Division, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan S7N 4H4, Canada b Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada Received 23 March 2007; received in revised form 8 August 2007; accepted 24 September 2007 Abstract N-myristoylation is a co-translational, irreversible addition of a fatty acyl moiety to the amino terminus of many eukaryotic cellular proteins. These myristoylated proteins in the cell have diverse biological functions such as signal transduction, cellular transformation and oncogensis. Known myristoylated proteins [Src family kinases, the catalytic subunit of cAMP-dependent protein kinase and calcineurin (CaN)] are either protein kinases or a protein phosphatases which modulate various cellular metabolic processes. Myristoylation is catalyzed by N-myristoyl- transferase (NMT) and is recognized to be a widespread and functionally important modification of proteins. The main objective of this review is to focus on the potential role of NMT and CaN in epileptic brain and its involvement in neuronal apoptosis. The findings on the interaction of NMT and CaN with various signaling molecules in epileptic chickens adds to our understanding of the mechanism of CaN signaling in neuronal apoptosis. Understanding the regulation of NMT by specific inhibitors may help us to control the action of this enzyme on its specific substrates and may lead to improvements in the management of various neurological disorders like Alzheimer’s disease, ischemia and epilepsy. # 2007 Elsevier Ltd. All rights reserved. Keywords: N-myristoyltransferase; Calcineurin; Calmodulin; Apoptotic factors; Cysteine proteases; p53; Epilepsy Contents 1. Introduction .................................................................................. 77 2. Myristoyltransferase in epilepsy..................................................................... 78 3. Cross-talk between N-myristoyltransferase and other signaling molecules ........................................ 79 4. Expression of CaN in epilepsy ..................................................................... 80 5. CaN interaction with proteases ..................................................................... 81 6. CaN interacts with p53 and Bcl-2 ................................................................... 82 7. Conclusion ................................................................................... 82 Acknowledgements ............................................................................. 83 References ................................................................................... 83 1. Introduction Epilepsy is one of the most common neurological problems worldwide. Important advances have been made in under- standing this neurological disorder in recent years, but the molecular and cellular mechanisms underlying the neuronal death remain to be explored. Ca 2+ acts as a second messenger in a number of different signaling pathways and plays a critical role in www.elsevier.com/locate/pneurobio Progress in Neurobiology 84 (2008) 77–84 Abbreviations: CaN, calcineurin; NMT, N-myristoyltransferase; NMDA, glutamate N-methyl-D-aspartate; SFKs, Src family kinases; CaM, calmodulin; CsA, cyclosporin A; Hsc70, heat shock cognate protein; MetAP, methionine aminopeptidase; NFAT, nuclear factor of activated T cells. * Corresponding author. Tel.: +1 306 966 7733; fax: +1 306 655 2635. E-mail address: rsharma@scf.sk.ca (R.K. Sharma). 1 Both authors contributed equally. 0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2007.09.004