Ionchannelopathy

Ion channelopathy（离子通道病）,Dr. Fang WangDepartment of Pharmacology,1,Ionic channelopathies,Diseases caused by disturbed function of ion channel subunits or the proteins that regulate themThese diseases may be either congenital (先天性，a mutation or mutations in the encoding genes) or acquired (获得性，autoimmune attack on an ion channel),Sodium channelopathiesPotassium channelopathiesCalcium channelopathiesChloride channelopathies,2,Increasingly recognized as important cause of disease (30 diseases). Numerous mutation sites may cause similar channelopathy e.g. cystic fibrosis, where 1000 different mutations of cystic fibrosis transmembrane conductance regulator (CFTR) described,3,Channelopathies,Why are channelopathies so important?,Some channelopathies have serious consequences for the well-being of affected patientsIon channel dysfunction is a distinctive pathophysiological feature that can in principle be corrected pharmacologicallyChannelopathies illustrate functional roles of various ion channelsChannelopathies allowed cloning of multiple important ion channel proteins,4,Channel Function,Ion channels are not open continuously but open and close in a stochastic or random fashion. Ion channel function may be decreased by decreasing the open time (o), increasing the closed time (c), decreasing the single channel current amplitude (i) or decreasing the number of channels (n).,I. Production,II. Processing,III. Conduction,IV. Gating,Molecular Mechanisms of Channel Disruption,Channelopathies,Copyright restrictions may apply.,Human Channelopathies,Ptacek, L. J. et al. Arch Neurol 2004;61:1665-1668.,Channelopathies,But new additions:Absence epilepsy (癫痫小发作) and Febrile convulsions (高热惊厥） GABAA subunit GABA channelPainful neuropathy Nav1.7 Na channelFurthermore: Numerous diseases seen in KO animals that mimic human diseasesDeafness L-type VGCC channel,Channelopathies-general characteristics,Although mutation is continuous, the disease may be episodic, such as periodic paralysis (周期性麻痹）or progressive, like spinocerebellar ataxia (脊髓小脑共济失调）.Abnormalities in same channel may present with different disease states.Lesions in different channels may lead to same disease, e.g. periodic paralysis.,Disease caused by defective sodium channel genes and proteins,Sodium channelopathies,The channelopathies of human heart,Hyperkalemic periodic paralysisParamyotonia congenitaK+- aggravated myotoniaAtypical myotonia,Long QT syndrome type 3,The channelopathies of human skeletal muscle,10,Twenty years ago, a quarterhorse named “Impressive” won all of the titles of his class. He was the top-winning, top-producing Quarter Horse stallion (千里马) of all time. As a breeding stallion, he turned out champion after champion. Many of Impressives offspring bore the same dramatic physical stature as their sire.,Soon his progeny (后裔) were seen to be affected by a strange muscular twitching that often left them temporarily unable to move.Usually mis-diagnosed as colic, these episodes varied widely in degree and duration.but all had one factor in common, their pedigree（血统）. As a result, many people now know hyperkalemic periodic paralysis (HYPP) by its more common name: Impressive Syndrome.,This particular defect is a dominant (显性) condition, meaning that at least half of the affected horses offspring will be affected as well. In the words of one prominent Quarter Horse trainer, this discovery was one of the most devastating things that ever hit the horse industry.,In horses, it is characterized by sporadic attacks of muscle tremors, weakness and collapsing. These HYPP attacks can also involve loud breathing noises from paralysis of the muscles of the upper airway. Sudden death can occur in these horses from heart failure or respiratory muscle paralysis. Electromyography (EMG): spontaneous activity from muscles under no stimulation.Because these muscle tremors happenin other diseases besides HYPP, those results were not enough evidence to give an accurate diagnosis.,Hyperkalemic periodic paralysis(HyperKPP，高血钾性周期性麻痹),Attacks of muscle weakness or paralysis, alternating with periods of normal muscle function. Attacks usually begin in early childhood. Multiple daily attacks are not uncommon. Attacks typically last only 1 to 2 hours, but can sometimes last as long as a day. They tend to occur while resting after exercise or fasting (禁食).,Humans also can have HPP (HyperKPP),15,Risks: include a family history of periodic paralysis. Disorders that cause intermittent (间歇性) episodes of paralysis as their primary effect are uncommon. More commonly, an intermittent episode of paralysis or weakness is a symptom of another disorder. Hyperkalemic periodic paralysis occurs in approximately 1 in every 100,000 people. Men are affected more often than women and usually have more severe symptoms.,Weakness/paralysis Most commonly located in the shoulders and hips(臀部) Arms and legs may also be involved Occurs intermittently May occur on awakening May be triggered by rest after exercise May be triggered by fasting Usually lasts for less than 2 hours Spontaneous recovery of normal strength between attacks Normal alertness during attacks,Human Symptoms,SCN4A mutation: linkage to the sodium channel expressed in muscle. The mutation causes single amino acid changes in parts of the channel which are important for inactivation. In the presence of high potassium levels, including those induced by diet, sodium channels fail to activate properly.,17,Membrane-folding model of the Na channel subunit and locations of missense mutations associated with hyperkalemic periodic paralysis (HyperPP;), paramyotonia congenita (PMC; (), and potassium-aggravated myotonia (PAM;).,18,Abnormal inactivation : increase in channel opening frequency,Abnormal activation：Half activation voltage shifts to leftward,19,Physiological condition,Action potentials end-plate potentials at the NMJ sodium ions to enter via Nav1.4 depolarize the muscle cells the entry of calcium from the sarcoplasmic reticulum contraction. Nav1.4 fast inactivation gate plugs the sodium pore very quickly after it opens prevents further entry of sodium; potassium ions will leave the muscle cells repolarize the cells pump calcium away from the contractile apparatus relax.,20,Mutations:Between transmembrane domains III and IV the fast inactivation gate of Nav1.4. Cytoplasmic loops between the S4 and S5 helices of domains II, III and IVthe binding sites of the inactivation gate.Mutations disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis.,HyperKPP,21,Treatment,Glucose or other carbohydratesIntravenous calciumDiuretics: furosemide, chlorothiazideIntravenous glucose and insulin (stimulates potassium uptake into the cell by the Na-K ATPase)A high-carbohydrate dietAvoidance of other known attack triggers.,22,Paramyotonia congenita (PMC)钾离子恶化性肌强直病,Eulenburg disease Rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotoniaIt becomes worse with exercise and cold temperatures, some patients have reported that eating ice cream leads to a stiffening of the throat, carrots and watermelon are able to induce these symptoms,23,Membrane-folding model of the Na channel subunit and locations of missense mutations associated with hyperkalemic periodic paralysis (HyperPP;), paramyotonia congenita (PMC; (), and potassium-aggravated myotonia (PAM;).,失活门控部件接受位点,电压感受器,24,Abnormal inactivation: Inactivation speed decrease Reactivation speed increase,25,Mutation of SCN4A: affect fast inactivation of the encoded sodium channel. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channels kinetics.,26,Myotonic muscle: hyperexcitable and able to produce action potentials for the duration of the stimulus pulse.,Normal muscle: a single action potential, due to inactivation of sodium channels, preventing their further activation even during depolarization.,27,LQT3(第三类长QT间隔症),A rare inborn heart condition in which delayed repolarization of the heart following a heartbeat, increases the risk of episodes of torsade de pointes (TDP, a form of irregular heartbeat that originates from the ventricles). These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation. Episodes may be provoked by various stimuli, depending on the subtype of the condition,28,29,30,Mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5).,31,The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. The mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.,32,Disease caused by defective potassium channel genes and proteins,Potassium channelopathies,Andersen-Tawil syndromeNonsyndromic sensorineural deafness type 2 Episodic Ataxia,33,AndersenTawil syndrome(Andersens综合征),An autosomal dominant pattern genetic disorder.Long QT syndrome an unusually small lower jaw (micrognathia, 小颌畸形)low-set ears (低位耳)an abnormal curvature of the fingers (clinodactyly, 手指弯曲变形),34,Andersen-Tawil syndrome,KCNJ2 gene: forms a channel that transports potassium ions into muscle cells to maintain the normal functions of skeletal musclesMutations in the KCNJ2 gene: alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane.,36,17号染色体长臂的2区3带,37,an autosomal dominant form of progressive hearing loss,Nonsyndromic sensorineural deafness type 2神经性耳聋,38,KCNQ4: play a critical role in the regulation of neuronal excitability, particularly in sensory cellsof the cochlea,39,Episodic Ataxia(阵发性共济失调）,An autosomal dominant disorder characterized by sporadic bouts of ataxia (severe discoordination) with or without myokymia (continuous muscle movement, 肌纤维颤动),40,KCNA1: Encodes Kv1.1. Expressed in basket cells and interneurons that form GABAergic synapses on Purkinje cells. Aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from the cerebellum.,41,Calcium channelopathies,Hypokalemic periodic paralysisFamilial hemiplegic migraineEpisodic ataxia type IISpinocerebellar ataxia VI,42,Hypokalemic periodic paralysis（低钾性周期性麻痹）,Muscle weakness or paralysis with a matching fall in potassium levels in the bloodTriggered by strenuous exercise followed by rest, high carbohydrate meals, meals with high sodium content, sudden changes in temperature, and even excitement, noise or flashing lights,43,CACNA1S (Cav1.1) mutations:loss-of-function mutation, cannot open normally.the channel has a reduced excitability and signals from CNS are unable to depolarize the muscleparalysis. low extracellular K+ concentration will cause the muscle to repolarize to the resting potential more quickly. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax.,44,Treatment,Avoiding carbohydrate-rich meals, strenuous exercise and other identified triggersacetazolamide (Diamox) or another carbonic anhydrase inhibitor，potassium-sparing diuretics such as spironolactone.drinking KCl dissolved in water.,45,Familial hemiplegic migraine（家族性偏瘫性偏头痛）,An autosomal dominant classical migraine subtype that typically includes hemiparesis (weakness of half the body) during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizuresCACNL1A4：P/Q-type calcium channel subunit,46,Chloride channelopathies,Myotonia congenitaBartter syndromeCystic fibrosis,47,Mutations in the carboxy terminus of CLC transport proteins lead to a number of diseases. The schematic represents the region immediately following helix-R above. Diseases from mutations lead to Bartters Syndrome (ClC-Kb), Myotonia (ClC-1), Dents Disease (ClC-5), juvenile epilepsy (ClC-2), osteopetrosis (ClC-7).,48,Myotonia congenita（先天性肌强直）,SymptomsDelayed relaxation of the muscles after voluntary contraction (myotonia)Rigidity, stiffness, hypertrophy (enlargement), sluggishness (迟缓) of the muscles, transient weakne