Question

Find the channel that caused a channelopathy disease. Explain the structure of the channel you find and how it works?

Answer 1

Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired.
There are many distinct dysfunctions that are known to be caused by ion channel mutations. The genes for the construction of ion channels are highly conserved amongst mammals and one condition, hyperkalemic periodic paralysis. It was first identified in the descendants of Impressive, a registered Quarter Horse.

The channelopathies of human skeletal muscle include hyper- and hypokalemic periodic paralysis, myotonia congenita and paramyotonia congenita.
Channelopathies affecting synaptic function are a type of synaptopathy.

Channelopathies are diseases that develop because of defects in ion channels caused by either genetic or acquired factors. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. Consistent with the distribution of ion channels throughout the human body, ion channel defects have been implicated in a wide variety of diseases, including epilepsy, migraine, blindness, deafness, diabetes, hypertension, cardiac arrhythmia, asthma, irritable bowel syndrome, and cancer.
Ion channels:
Ion channels are transmembrane proteins which allow the passive flow of ions, both in and out of cells or cellular organelles, following their electrochemical gradients. Because the flux of ions across a membrane results in electrical currents, ion channels play a key role in generating membrane potential and function in diverse cellular activities, such as signal transduction, neurotransmitter release, muscle contraction, hormone secretion, volume regulation, growth, motility, and apoptosis. Ion channels can be classified according to the types of ions passing through them, the factors of their gating, their tissue expression patterns, and their structural characteristics. Ion channels typically exist in one of the three states: open, inactivated closed , and resting closed. The gating of ion channels is controlled by diverse factors, such as membrane potential, ligands, second messengers, light, temperature, and mechanical changes. Ion channels are formed from either a single protein or, more commonly, from an assembly of several subunits, each a protein encoded by a different gene. More than 400 ion channel genes have been identified. Further diversity comes from a number of mechanisms, which include the use of multiple promoters, alternative splicing, posttranslational modifications, heteromeric assembly of different principal subunits, and interaction with accessory proteins.

Channelopathies in the nervous system:
Ion channels are fundamental in neuronal signaling and thus, channelopathies can be found in a large and growing number of nervous system disorders. Among the first genetically characterized and best-understood channelopathies are those who lead to primary skeletal muscle disorders. These muscle disorders exhibit a clinical spectrum ranging from myotonia to flaccid paralysis. Patients with myotonia congenita present with attacks of extreme muscle stiffness because of delayed relaxation caused by sustained electrical activities in muscle. Both the dominant and the recessive types of the disease are caused by loss-of-function mutations in a single gene, CLCN1, which encodes the skeletal muscle chloride channel, ClC-1. ClC-1 channels stabilize the resting membrane potential and contribute to membrane repolarization after action potentials in skeletal muscle cells. When action potentials are elicited, potassium ions flow out of the cell and into the extracellular fluid and the transverse tubular system. According to the Nernst equation, the membrane tends to depolarize as extracellular potassium levels rise. Functional loss of ClC-1 channels reduces the inward chloride current required to compensate for the depolarization induced by potassium accumulation in the transverse tubules, thus resulting in spontaneous repetitive firing of action potentials and a slower rate of repolarization.
Channelopathies in Cardiovascular system:
Cardiac action potentials are generated from a delicate balance of several ionic. When this balance is disturbed by ion channel dysfunction, life-threatening cardiac arrhythmias may occur. Cardiac channelopathies are likely responsible for approximately half the sudden arrhythmic death syndrome cases and for at least one out of five sudden infant death syndrome cases. Mutations in calcium, sodium, potassium, and TRP channel genes have been identified to cause a variety of cardiac arrhythmic disorders, and polymorphisms have been suggested to be risk factors.
Channelopathies in Respiratory system:
There are a number of ion channels expressed in airway cells which have been evaluated, the function of which may contribute to pathogenic conditions, but channelopathies in the respiratory system may not represent common pathologies in Asian populations. This is partly because cystic fibrosis -the first identified and the most common channelopathy that affects the respiratory system in Western populations-is rarely diagnosed in Asian people. CF is the most prevalent genetic disorder in the Caucasian population, with an incidence of approximately 1 in 2,500 live births. Patients with CF are vulnerable to severe and chronic pulmonary infections and inflammation, which lead to irreversible airway damage and respiratory failure in most cases. CF exhibits a broad spectrum of symptoms: mild forms can be nearly asymptomatic, being diagnosed in middle age as affecting a single organ, whereas severe forms manifest not only in airways but also in digestive and reproductive systems, with some of the symptoms occurring as early as in the prenatal period.
CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. CFTR functions as a chloride channel in the apical membrane of epithelia, where the channel controls the volume of liquid on epithelial surfaces by secreting chloride and inhibiting sodium absorption. More than 1,600 mutations in the CFTR gene have been identified. These mutations, which produce varying functional effects on CFTR, are considered to cause an abnormal transepithelial flux of chloride and sodium, which is accompanied by the passive flow of water and results in liquid depletion on the epithelial surface layer. Depletion of the airway surface liquid, which impairs ciliary function and mucociliary clearance, may lead to recurrent pulmonary infections and chronic inflammation in CF patients. Increased knowledge of the molecular pathophysiological mechanism underlying CF has led to a variety of active clinical trials to identify targeted treatments, such as channel-specific drugs and gene therapy.
Channelopathies in endocrine system:
Electrical activity plays an essential role in insulin secretion from the pancreatic β cell. Endocrine cells, like neurons and other excitable cells, use the electrical activity of ion channels to maintain or regulate various physiological functions. Defects in ion channels have been increasingly shown to cause endocrine disorders, including those not generally thought of as channelopathies.
Channelopathies in immune system:
Antibodies against ion channels and associated proteins expressed on the surface of neurons or muscle cells have been implicated in a variety of neurological pathologies ranging from myasthenia gravis or MG to certain forms of encephalitis. Typical paraneoplastic antibodies generally target intracellular antigens and are not likely pathogenic. However, antibodies responsible for autoimmune channelopathies, often arising under paraneoplastic conditions, directly affect the kinetics and/or membrane density of ion channels or damage cells expressing the channels, which accounts for the favorable response shown by most patients to immunotherapies. Autoimmune channelopathies have been increasingly found in all age group.
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