Introduction
The proper function of ion channels is essential to the regulation of the central nervous system (Lerche, Jurkat-Rott & Lehmann-Horm 2001). Voltage-gated and ligand-gated ion channels possess qualities which enable communication between neurones in the central nervous system. Ion channels are small proteins found on the cell membrane and are regarded as transmembrane proteins as they cross the entire membrane making it permeable to specific ions (Graves 2006).
The malfunctioning if these ion channels poses a real threat to the normal communication of the cells and, in-turn causes neurological disorders such as epilepsy (Lerche et al. 2012). This report will outline the relationship between ion channels and certain genetic epileptic disorders as understanding this relationship will greatly impact further research and development of new drugs and techniques to combat these disorders.
For the purpose of this report and linking the abnormal function of ion channels and epilepsy, the focus will be on genetic disorders influencing voltage-gated ion channels. This report will extensively include (as an example) but is not limited to ‘generalised epilepsy with fibrile seizures plus type 1’ (GEFS+) and ‘generalised epilepsy with paroxysmal dyskinesia (GEPD).
Epilepsy and the Influence of Genes
Epilepsy is a neurological disorder resulting in seizures caused by misfiring of neuronal activity within the central nervous system (D’Adamo et al. 2013). This phenomenon is known as hyper-excitability in the nervous system. Ion channels are thought to be responsible for the abnormal neurological function and the study of these transmembrane protein structures is essential for understanding epilepsy and possible cures for the symptoms and the disorder itself.
Epileptic symptoms can be caused by a multitude of disorders ranging from tumours to genetic abnormalities. In regards to genetic causations, it is believed that just over 25% of genes causing epilepsy regulate ion channels (Oyrer et al. 2018, p. 142) and it is well established that voltage-gated ion channels such as sodium and potassium ion channels are main contributors to epilepsy as voltage-gated ion channels play a large role in the initiation of action potentials (Oliva, Berkovic & Petrou 2012).
These voltage-gated ion channels include Sodium (Na+) and Potassium (K+) ion channels and they are extremely important in the communication between neurones throughout the central and peripheral nervous system. They allow the passive transport of these ions in and out of the neurone through the cell membrane (Graves 2006). Voltage gated ion channels comprise of alpha and beta subunits and are activated (opened) as a result of an electrical signal allowing for the translocation of ions. When one of these genes facilitating the regulation of these ion channels is altered, the structure of the protein itself may change, thus affecting the productivity of the ion channel. The relationship between poor functioning sodium ion channels and epilepsy is observed extensively in GEFS+ Type 1 and potassium ion channel abnormalities are shown to cause GEPD.
Sodium Ion Channels and GEFS+ Type 1
Sodium (Na+) ion channels allow the passive movement of positive sodium (Na+) ions into the negatively charged interior of the neurone (cytoplasm). These Ion channels open up their M-gates when an all-or-nothing threshold is met. This allows the passive flow of positive sodium ions into the cell making the cell depolarised. This mechanism allows for the facilitation of the desired action potential.
If this specific sodium ion channel does not work accordingly, the entire process will have negative health implications including the individual acquiring epileptic disorders (Armijo et al. 2005). Generalised epilepsy with fibrile seizures plus type 1 (GEFS+) is one of these epileptic disorders. GEFS+ type 1 is a rare epileptic disorder that affects children sometimes upwards of six years old and is commonly characterised by frequent fibrile seizures (George 2005).
A gene believed to be responsible for GEFS+ type 1 is SCN1B, which has a point mutation substituting a tryptophan residue for a cysteine residue (Lerche, Jurkat-Rott & Lehmann-Horm 2001). As Lerche, Jurkat-Rott & Lehmann-Horm (2001, p. 153) state, this completely alters the ‘secondary structure of a beta-subunit’ by changing one of the cysteine-cysteine bonds (disulphide bond). This limits the function of this specific subunit resulting in the slowed closing of the H-gate thus allowing more sodium ions into the cell than anticipated causing rapid depolarisation beyond the normal peak of action potentials (~40mV) resulting in hyper-excitation.
This gene works along side SCN1A, SCN21 and the GABA A receptor subunit genes (KEGG eds. 2018). Although, it’s believed that in this specific type of epilepsy, the substitution of the Cytosine amino acid by the SCN1B gene is a crucial cause for the disorder. Brackenberry et al. (2013) studied the gene with SCN1B-null mice and observed that the mice exhibited sever epileptic seizures pointing to a hypothesis that the SCN1B gene in humans is a main contributor to GEFS+ type 1 as it alters the voltage-gated sodium ion channel. Although the results were observed in mice, they are objectively credible in regards to simulating human responses to the defective gene as the human genome shares many significant similarities with the genomes of rodents.
It is also known that in individuals with this mutation in the beta-subunit, the effectiveness of the anti epileptic drug phenytoin is limited (Lucas et al. 2005). This increases the need to investigate sodium ion channels further as physiological knowledge will greatly aide research and development into new anti epileptic drugs and treatments.
Potassium Ion Channels and Generalised Epilepsy
Potassium (K+) ion channels allow the passive flow of potassium ions from within the cell, to outside of the cell during the repolarisation stage of an action potential. Generalised epilepsy and paroxysmal dyskinesia (GEPD) is a disorder caused by a mutation in potassium ion channels (Chen 2005). GEPD is characterised by where an individual experiences symptoms of both generalised epilepsy and paroxysmal dyskinesia simultaneously. The disorder is believed to be as a result in the alteration of the gene KCNMA1 (Du et al 2005), which causes a mutation in the potassium ion channel disrupting this normal repolarisation phase.
The mutation occurs in the alpha-subunit of the ion channel and this causes a rapid repolarisation to occur when the channel is opened. The rapid repolarisation causes hyper excitability causing the symptoms of generalised epilepsy in GEPD (Du et al. 2005).
Du et al. (2005) identified the KCNMA1 gene as the cause for GEPD by a large scale scan of the human genome surveying micro-satellites. Du and his associates discovered that the gene responsible was located at the locus of 10q22 and concluded that the gene was KCNMA1. They hypothesised that the an aspartic residue is substituted with a glycine residue leading to a mutation in the protein structure which ultimately limits the proteins ability to function correctly.
Potassium channels are also linked to other idiopathic epileptic disorders such as benign familial neonatal convulsions (BFNC) (Singh et al. 1998) where newborn babies experience tonic-clonic seizures. The gene responsible is thought to be KCNQ2 (Lee et al. 2017: Yazidi, Shevell & Srour 2017) and like in GEPD, the gene in BFNC alters the protein structure of the potassium ion channel.
Challenges and Future Developments
Due to the immense size of the human genome, it is clear that there may be many unknown genetic causes of epilepsy that are still yet to be explored. George (2005) acknowledges that there may be other disorders associated with sodium ion channel mutations but are still unknown. It is clear that despite our large current understandings of the physiological mechanisms associated with voltage-gated ion channels, it is inevitable that our contemporary knowledge is still vastly limited. Lerche et al. (2012) state that most forms of epilepsy still have an unknown molecular explanation despite extensive research. Future research projects focusing on sodium and potassium voltage-gated ion channels may hold the key information to these questions and the knowledge obtained will greatly benefit the pharmacological and clinical communities alike. Increased knowledge of these ion channels is essential for the development of new drugs to combat epileptic disorders thus the importance of increased research.
Conclusion
Through the brief investigation of some voltage-gated sodium and potassium ion channel mutations, it is clear that the mutations in these ion channels are large contributing factors to certain epileptic disorders such as GEFS+ and GEPD. The malfunctioning of these voltage-gated ion channels can be detrimental to an individual and further research is needed to create a more thorough understanding of the physiological mechanisms present. Both sodium and potassium voltage-gated ion channels are extremely important to neurological function, which is why there is a necessity for future projects focusing on this topic in neuroscience.
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