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Structure and Function of the Chloride Channel: Myotonia Congenita - Term Paper Example

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The paper "Structure and Function of the Chloride Channel: Myotonia Congenita" focuses on the mutations involving chloride ion channelopathy. Myotonia congenita is the most common skeletal muscle channelopathy caused by mutations in the skeletal muscle voltage-gated chloride channel gene CLCN-1…
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Structure and Function of the Chloride Channel: Myotonia Congenita
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MYOTONIA CONGENITA By Introduction Ion channels consist of transmembrane glycoprotein pores, and they play a critical role in the excitability of mammalian cells; usually through the flow of ions in out of the cell (Bernard & Shevell 2008). Channels exist in three different sates: open, closed or inactive. They are composed of different subunits and each subunit is coded for by specific genes (Bernard & Shevell 2008). An ion channel can be either of the voltage gated class or the ligand gated class. We have several genetic diseases that are caused by abnormalities in ion channels (channelopathies). This paper will focus on the voltage gated chloride channel channelopathy called Myotonia congenita that affects skeletal muscles. The paper will examine how defects in the chloride channel ion genes contribute to this disease, related cellular effects and how it affects the skeletal muscles of affected individuals. Excitability of membranes is vital for muscle function and is usually regulated by Voltage gated ion channels. Therefore, it is not surprising that ion channels are involved in the physiopathology of disorders of the skeletal muscle (Rott, Lerche & Horn, 2002). It will also exemplify research that is currently being conducted on this disorder. According to Zhang (1999), myotonia occurs due to delayed relaxation of muscle after a voluntary contraction or mechanical stimulation. There are dystrophic and non dystrophic forms of myotonia which can be identified according to their clinical features. The non dystrophic myotonia includes three main types: myotonia congenita, paramyotonia congenita and hyperkalemic periodic paralysis. Clinical electrophysiological studies of patients with these diseases revealed repetitive electrical discharges (myotonic runs). Normally, the myotonic runs occur in response to electrical and mechanical stimulation in muscles. Myotonia is the stiffness noticed upon initiation of movement. Myotonic dystrophy is also another myotonic disorder characterized by multisystem involvement. Patients with myotonic dystrophy have cataracts, cardiac arrhythmias, skeletal muscle problems and other endocrine abnormalities (Harper & Ptacek et al. as cited in Zhang 1999). However, Myotonia congenital (MC), a subtype of Myotonia, is a genetic muscle disease associated with defects in the musculoskeletal chlorine voltage gated ion channels C1C-1. Pathologically, MC is an inheritable skeletal muscle disorder that results from the diminished activity of the sarcolemmal voltage gated chloride ion channels. The syndrome may be transmitted by either an autosomal dominant (Thomsen’s disease) or recessive generalized myotonia (Becker’s myotonia) mode of inheritance (Thomsen & Becker as cited in Zhang 1999). Ptacek et al. argued that patients with MC normally have painless myotonia that is improved by exercise, a phenomenon termed as “warm up exercise” (Zhang 1999). Individuals affected by this disorder usually have well developed muscles. Histochemical studies of fiber sub types have demonstrated a complete absence of type 2B muscle fibers in MC patients with Thomsen’s disease (Crews et al. as cited in Zhang 1999). The onset of Thomsen’s disease occurs within the first two years of life and muscle stiffness is usually the predominant symptom. These patients do not have periodic paralysis, which distinguishes Thomsen’s disease, from hyperkalemic periodic paralysis and paramyotonia congenita. Cloning has showed that, there is a substitution of glycin 230 by glutamic acid (G230E), between two crucial segments (D3 andD4) of the voltage gated chloride ion channel. This dramatically affects the properties of the ion channel...the G230E mutation causes a substantial change in the selectivity of anions and cations; as well as a key change in the rectification of current-voltage relationship (Fahlke, Beck & George 1997). Another type of autosomal dominant Myotonia congenita called Acetalozamide Responsive MC, also exits (Trudell et al. & Rudel as cited in Zhang 1999). Patients with this condition have painless muscle stiffness, usually provoked by fasting and an oral administration of potassium but relieved by carbohydrate containing foods. Muscle biopsies have shown the presence of type 1, 2A and 2B, fibers. On the contrary, typical Thomsen’s MC patients lack type 2B fibers. During MC classification, Becker found that many families for which MC exhibited recessive mode of inheritance presented a somewhat different clinical picture (more severe) that does not quite follow the classical Thomsen’s disease. Becker’s MC resembles Thomsen’s disorder with the warm up sign but on the contrary, it is transmitted as an autosomal recessive trait (as cited in Zhang 1999). Clinical studies have also revealed that Becker’s MC and Thomsen’s MC have another difference, periodic paralysis, which occurs in Becker’s MC only. How Voltage Gated Chloride Channel contributes to MC at the cellular level Ion channels comprise of a class of macromolecular protein tunnels that span the lipid by-layer of the cell membrane. This allows for ions to flow in and out of the cell in a very efficient fashion (Felix, 2000). The flow of ions generates electrical currents large enough to produce rapid changes in the trans membrane voltage, which is the electrical potential difference between the cell’s intracellular and extracellular environments (Felix, 2000). The chloride channels comprise of a large group of proteins that selectively permits the passage of anions but excludes cations. These channels can be classified in to three super families. The first super family is the voltage gated chloride channels C1C family (Jenstec et al as cited in Zhang 1999). The second includes the ATP binding chloride channels: cystic fibrosis transmembrane regulator (CFTR) and P glycoprotein (Riodan et al. & Hide eta l. as cited in Zhang 1999). The third consists of ligand gated chloride channels such as gamma amino butyric acid (GABA) and glycerine receptors. Voltage gated chloride channels are unibiquios and play a critical role in many physiological and pathological processes (Hille as cited in Zhang 1999). The active site of an ion channel is an aqueous pore that selectively permits passage of chloride ions while excluding sodium and potassium ions. The skeletal muscle cell has a resting electric membrane potential of approximately -80Mv and specific membrane bound ions mediate selective membrane permeability (Bryant as cited in Zhang 1999). The channel is highly sensitive to changes in electric potential of the membrane. When the neurotransmitter acetyl choline is released at the neuromuscular junction, acetyl choline receptors on the post synaptic membrane are activated triggering the change of the membrane potential. This depolarization activates voltage gated sodium ion channels permitting an inward flow of sodium ions. This leads to a rapid depolarization of the membrane. In a span of milliseconds, the voltage dependent potassium ion channels also open, releasing potassium ions to the extracellular environment. At the same time, voltage dependent chloride channels open permitting chloride influx into the cell. Consequently, the sodium channel is inactivated permitting the repolarization of the membrane. In skeletal muscle, chloride currents account for 80% of the resting conductance, and this serves to clamp the resting membrane potential close to the chloride equilibrium potential. In normal skeletal fibers, the chloride conductance tends to clump the membrane equilibrium potential close to the chloride equilibrium potential of -80Mv. The lack of this shunt in myotonic fibers leads to an after depolarization and subsequent repetitive activity causing the delay in muscle relaxation as seen in MC. As stated earlier, there are two forms of MC: autosomal-recessive Becker disease and autosomal dominant Thomsen disease. The two diseases are brought about by mutations in the gene CLCN1 that codes subunit for the skeletal muscle. The mutation leads to the chloride ion channel malfunction. The chloride conductance, mediated through the activation of C1C-1 channels, is greatly reduced in patients with MC. Chloride conductance contributes significantly to the resting membrane, and helps to inhibit electrical activity. Malfunctions in this ion channel, cause muscle hyper excitability that delays muscle relaxation (Kilic & Puljack 2006). Under normal circumstances, end of muscle contraction is initiated when chloride ion channel opens up allowing the entry of chloride ions in the cell. In diseased subjects, the channel is usually unstable causing continued muscle contractions, which are the whole mark of Myotonia. Functional characterization of CLCN1 mutations Most MC causes a considerable decrease in chloride conductance in the affected muscle (Adrian & Marshall as cited in Zhang 1999); thus, the mutations associated with MC phenotype must affect channel function, protein processing or both. Therefore, functional characterization of these mutations is vital in comprehending the molecular manifestation of MC. Dominant mutations and some recessive ones have been fully studied and have shown to cause the following functional defects; Decrease in C1C-1 conductance, a depolarization shift in the voltage dependence of opening or an increase in cation permeability. The right wide shift of open probability of C1C-1 channels; is a common defect associated with MC associated mutations. However, no correlation between the locations of these mutated residues has been demonstrated. Structure and Function of the chloride channel After cloning the gene that encodes proteins for this channel, it has been estimated that the protein structure contains twelve membrane spanning domains (based on the hydropathic plot), with an additional thirteenth domain that may not cross the membrane (Jenstch et al as cited in Zhang 1999). Both the N and C termini and the thirteenth domain are located in the cell (Grunder et al. as cited in Zhang 1999). The linker region between D8 and D9 is likely to be located on the extracellular side because of an N linked glucosyltion site. Each C1C-1 subunit is a 110 KD protein, composed of 13 putative transmembrane domains. However, conflicting evidence supports at least two transmembrane topologies thus; knowledge about CIC-1 is still limited. Current Research on voltage gated chloride channel Despite the fact that many CLCN1 mutations have been identified from MC patients, many other mutations may still exist in MC patients. The National Center of Neurological Disorders and Stroke (NCNDS) is currently investigating the molecular level mechanisms of the defective gene in Myotonia congenita; and causes of some specific symptoms of the disorder. Additional research uses animal studies of the disorder to test potential drug developments (Brown 2011). Elsewhere, Wright State University Scientist has been given a grant amounting to $53 million dollars to conduct research on Myotonia congenita. The muscular dystrophy association acts as the donor for Professor Mark Rich of Wright State University in Dayton, Ohio taking effect from 1st February 2011. Professor Rich intends to study the disease process of Myotonia congenita. Rich’s goal is to determine the molecular mechanism underlying the exercise effect of MC. His team postulates that a single protein may be responsible for the turning on during exercise causing the reduction in stiffness. In case the findings from the research successfully discover such a protein, then the protein might be potentially targeted and exploited into turning on all the time while providing symptomatic relief to individuals with the disease. Conclusion It has been noted that genetic mutations in the genes that encode chloride, sodium, potassium and calcium channels of the skeletal muscles result in the periodic paralyses, the non dystrophic Myotonias and the ryanodinopathies. However, Myotonia congenita is the most common skeletal muscle channelopathy caused by mutations in the skeletal muscle voltage gated chloride channel gene CLCN-1 (Platt & Giggs 2009). Myotonia congenita is mainly characterized by slow skeletal muscle contractions after a voluntary contraction. The disorder occurs in two forms: autosomal dominant (Thomsen) and autosomal recessive (Becker). Becker type is the most common. Thomsen’s disease is rare and mild. The symptoms associated with this disorder normally appear in early childhood. However, the symptoms vary between individuals. Symptoms in early childhood may include difficulty swallowing, gagging and stiff movements that improve when repeated. Myotonia congenita may lead to several complications like aspiration pneumonia (caused by difficulties in swallowing), frequent choking or gagging in infants, abdominal muscle weakness and chronic joint problems. The autosomal recessive disorder (Becker) requires two copies of the gene to be present for it to occur (Kaneshiro 2010). On the other hand, the autosomal dominant disorder (Thomsen) requires one of the parents to carry the defective gene (Kaneshiro 2010). A lot of studies on the mutations involving chloride ion channelopathy have been carried out. However, more research needs to be done to unravel pathomechanisms of chloride ion channel channelopathy. Such studies may discover novel therapeutic targets for these disorders. Professor Rich of Wright State University in Dayton is currently researching on the possibilities of identifying such therapeutics. The National Center of Neurological Disorders and Stroke is also championing research on pathomechanisms and potential therapeutics. People with mild MC can manage their conditions without medication but in severe cases treatment is usually recommended. Drugs that have been used to treat Myotonia include sodium channel blockers like procainamide, phenytoin and mexiletine, tricyclic anti depressants drugs such as clomipramine or imipramine, benzodiazepines, calcium antagonists, taurine and prednisone (Trip, Engelen & Faber 2011). References Bernard, G and Shevell, MI 2008, Channelopathies: A review. 38: 73-85 Brown, Jim 2011, Research News. Retrieved 1st, Dec. 2011 from http://quest.mda.org/news/mda-awards-135-million-research-grants Fahlke, C, Beck, C and George AL 1997, A mutation in the autosomal dominant Myotonia congenita affects pore properties of the muscle channel. PNAS, 1997 March18, Vol. 94, No. 6: 2729-2734 Felix, Ricardo 2000, Channelopathies: ion channel defects linked to clinical disorders. Journal of Medical Genetics. 37:729-740 Kilic, G and Puljack, L (2006), Emerging roles of Chloride channels in human disease. Bioscience Direct, 1762 (2006), 400-413 Kaneshiro, N 2010, Autosomal Recessive. Retrieved on 2nd Dec. 2011 from http://www.nih.gov/mediplus/ency/article/002052.htm Platt, Daniel and Giggs, Robert, Skeletal muscle channelopathies: new insights in periodic paralyses and non dystrophic Myotonias. Current Opinion in Neurology. 22: 000-000 Rott, KJ, Lerche, H & Horn, FL, (2002) Skeletal Muscle Channelopathies. Neurology Journal. 249:1493-1503. Trip, J, Engelen, BG, and Faber CG (2011), Treatment for Myotonia. Retrieved on 5th Dec. 2011 from.http://summaries.cochrane.org/CD004762/drug-treatment-for-myotonia-delayed-muscle-relaxation-after-contraction-in-muscle-diseases-such-as-myotonic-dystrophy-and-myotonia-congenita Zhang, J 1999, Myotonia congenita-associated chloride channelopathies: Mutations. Functions and structure. Thesis (Thesis Ph. D), University of Utah, Utah, USA. Read More
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