Ion channels are macromolecular proteins embedded in the cell wall, which governs the direction of ion flow inside and outside the cell, through either electrical gradient or concentration gradient. In the last ten years, combination of electrophysiological and molecular genetic investigations in the field of the cell molecular biology led to the exploration of the growing family of diseases caused by mutations in genes encoding voltage- and ligand-gated ion channels, the so-called channelopathies. In other words, diseases with diverse properties, which are associated with ion channel dysfunction and can be grouped together as Channelopathies.
Almost all ion channels have central ion selective pore surrounded by subunits. Each subunit contains four domains (I, II, III, IV) which in turn each contains six helical transmembrane units (S1...S6). Sodium and calcium have their domains covalently linked. Potassium channels are tetrameric but their domains are not covalently linked. Embrane depolarization will cause conformational changes of the proteins which leads to opening of the channel (pore), this allows movement of the ions through chanels. Thus any changes in the amino acid sequence of the ion channel proteins due to one or the other reasons will change the permeation properties of the channel.
Diseases Associated With Ion Channel Mutation
Since in channels are protein macromolecules, they are prone for changes in amino acid sequences so called as mutations, which is major cause of channelopathies. Other than genetic mutations, autoimmune, toxic, or iatrogenic are mechanisms that may be involved in the channelopathies. Included amongst the Channelopathies are intermittent diseases in people who are otherwise healthy and active (eg, epilepsy, migraine, arrhytmia), more debilitating illnesses (such as muscular disorders, deafness, blindness, Rasmussen's encephalitis), and even some rare disorders like periodic paralysis.
Up till now, various channels have found to shown the genetic mutations and other said mechanisms leading to channelopathies. The various channels that are discovered to chow the channelopathies are sodium channels, potassium channels, chloride channels, calcium channels, less selective ion channels, glycine receptor, nicotinic acetylcholine receptor, glutamate receptors, GABA receptors, and various transporters.
There is genetic change of the channel protein in locus of the specific gene present in regulation of the above said channels and receptors, leading to formation of the disease. These changes in the genetic material of these ion channels and receptors are liable for inheritance.
Following are the examples of the diseases associated with ion channel defects and their predicted genetic reason ;
1. Myotonia congenita (Thomson's disease) AD
2. Periodic paralysis (hyper and hypokalaemia) AD
3. Malignant hyperthermia AD
4. Long QT syndrome AD/AR
5. Cystic fibrosis AR
6. Heritable hypertension (liddle's syndrome) AR
7. Familial persistant hyperinsulinemic hypoglycemia of infancy AR
8. Generalized Myotonia (becker's disease) XL
R=Recessive=Dominant, XL=X-linked, A=Autosomal.
Cystic Fibrosis (CF)
CF is due to defect I chloride channel protein (CFTR) that governs the movement of chloride ions across the cell membrane. A deletion of phenylalanine at position 508(Delta 508) accounts for more than 70% and is associated with severe pancreatic insufficiency and pulmonary disease. Treatment utilizes replacement of chloride channel by gene therapy or protein delivery. Therapeutic option for CF is CFTR openers or blocked of sodium reabsorption by aerosolized amiloride.
Long QT Syndrome (LQTS)
This is one of the cardiac disorders, which is characterized by QT interval prolongation, and T wave abnormalities that causes ventricular arrhythmias and sudden death in children and adults. There are different kinds of LQTS depending upon the chromosome or gene, which is mutated viz., LQTS1, LQTS2, and LQTS3 etc. Drugs which blocks potassium channel e.g. quinidine, sotalol, erythromycin, sulfamethoxazole etc may also lead to LQTS but there is delay in opening of channel which causes prolonged QT interval.
Myotonic Diseases
These are clinically similar diseases, which are characterized by delayed muscle relaxation after muscle contraction or mechanical stimulation.
For e.g., hyperkaelemic periodic paralysis (HKPP), Paramyotonia congenita (paradoxical Myotonia), Myotonia congenital, Myotonia dystrophy, Malignant hyper metabolic syndrome (malignant hyperthermia MH). All these diseases are associated with defect in sodium channel.
Epilepsy
The recent research on gene mutation occurred in ion channels of the neurons has shown a possible role in the pathophysiology of the epilepsy. This corresponds to either ligand gated channels or voltage gated ion channels.
Generalized epilepsy with fibrile seizure plus (GEFS+) is due to defects in sodium channel. The seizures, which are encountered due to reduction in the threshold potential
i. e. more firing of neurons causes hyper excitation.
Benign infantile epilepsy results from voltage gated potassium channel defect.
Autosomal frontal nocturnal epilepsy: As the name suggests it is not sex chromosome linked mutation. Mutations in nicotinic acetylcholine receptors (nAchR) are responsible for this kind of epilepsy. Approaches adapted to treat disease are channel blockers and gene therapy.
Channelopathies Related To Muscle:
Mutations of voltage gated Na+, K+, Ca++, and Cl channels and ligand gated acetylcholine receptor produce syndrome that affect tone and strength of muscle whereas others cause muscle paralysis. Ataxia results due to voltage gated K+ and Ca++ channel malfunctioning in the cerebellum, which causes loss of muscle coordination. Congenital slow channel syndrome is caused due to malfunction of nAchR (as in frontal nocturnal epilepsy) patient suffer from weakness, fatigability and degeneration of muscle fibre. Treatment employed here is channel blockers or gene therapy.
Common Causes Of Channelopathies
As could be found out from the above examples that the most prominent reason for channelopathy is genetic mutations either single point mutation or whole gene mutation. However protein mutation or changes in the activity of non-mutated channel gene or proteins can also produce acquired channelopathy. One of the important causes of channelopathies is autoimmune attack. Whereas nerve injury or after drug treatment that perturbs cellular function also cause channelopathy.
Detection Of Channelopathies
There are number of techniques available at hand for the detection, and diagnosis of channelopathies. The techniques such as PCR (Polymerase chain reaction), multiplex PCR with dot blot hybridization can be used in the clinical diagnosis of disease and detection of carrier. Specimens, which are used in the detection and diagnosis, are blood, amniotic fluids etc.
Conclusion
Molecular diversity of ion channels is large therefore there are lot of possibilities of diseases with channelopathies. Newer techniques such as atomic resolution coupled with biophysical techniques have been helping in understanding structure and function of ion channels, study of kind of proteins involved and thus helps in understanding the complex biological processes and pathology of the diseases associated with them.
In future, with the aid of molecular and genetic studies in combination with electrophysiological and physical methods, more and more diseases will be recognized and the molecular basis of the pathophysiology of the diseases will be discovered. The clear understanding of the genes involved will help in designing the possible gene therapies and molecular modeling will aid with the possible therapeutic leads for the targeted treatment of the diseases.
-- The authors are with Pharmacy Group, Birla Institute of Technology and Science, Pilani