Sodium channel defect

Pseudohypoaldosteronism, PHA-I Sodium channel defect or MR mutation SCNN1A SCNN1B MR 12pl3 16pl3-pl2 600228 600760... 

Cannon SC, Brown RH Jr, Corey DP. A sodium channel defect in hyperkalemic periodic paralysis potassium-induced failure of inactivation. Neuron 1991 6 619-626. 

Several diseases involving dysregulation of MR function have been described although most of them are not causatively linked to the receptor itself. Pseudohypoaldosteronism for example is a syndrome of mineralocorticoid resistance characterized by urinary salt loss and dehydration. However, only very rarely mutations in the MR gene have been found in these patients so far. In most cases, this syndrome appears to be linked to defects in the subunits of the amiloride-sensitive sodium channel ENaC, a major target of mineralocorticoid action in the kidney. 

HCN4 encodes a pacemaker current in sinoatrial nodal cells mutations in sodium channel gene (SCN5A) cause conduction defects. 

Local anesthetics block the sodium channels, are cardiac depressants, and bring about a ventricular conduction defect and block that may progress to cardiac and ventilatory arrest if toxic doses are given. In addition, these agents produce arteriolar dilation. Circulatory failure may be treated with vasopressors such as ephedrine, metaraminol (Aramine), or mephentermine (Wyamine). Artificial respiration and cardiac massage may also become necessary. Among the local anesthetics, only cocaine blocks the uptake of norepinephrine, causes vasoconstriction, and may precipitate cardiac arrhythmias. 

In the pancreas and lung, a similar situation exists. In secretory mode, the CFTR passes chloride to the lumen (while a sodium channel is inactivated) this draws sodium ions across the tight junctions, in turn pulling water into the lumen (Figure 4.12). Again, a defective CFTR will halt water movement into the lumen, leading to viscous secretions. 

H. A sodium channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. J. Physiol. 

Featherstone DE, Fujimoto E, Ruben PC 1998 A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita. J Physiol 506 627-638... 

Hypokalemic periodic paralysis Due to defective gene for one type of DHPR. Hyperkalemic periodic paralysis Due to defects in a skeletal muscle sodium channel,... 

Local anesthetics block the sodium channels, are cardiac depressants, and bring about a ventricular conduction defect and block that may progress to cardiac and ventilatory arrest if toxic doses are given. In addition, these agents produce... 

The human body has a limited capacity to increase body stores of potassium. The major causes of hyperkalemia are excess potassium intake and mixed doses of potassium and sodium electrolyte solutions (Mahfoud et al. 2003), reduced renal losses (acute renal failure, end-stage renal disease, mineralocorticoid deficiency, potassiumsparing diuretics) and redistributions of potassium (hemolyses, necrosis, muscle injury, catecholamine antagonists, insulin deficiency, abnormal skeletal muscle sodium channels) (Peterson 1997). Increased intake by itself is rarely the sole cause of significant hyperkalemia. However, sustained hyperkalemia usually indicates an underlying defect in renal potassium excretion or impaired potassium distribution (KCl supplements or salt substitutes). The... 

The genetic defect knoivn as hyperkalemic periodic familial paralysis" causes skeletal paralysis and hyperkalemia. In this disease, only one of the sodium channels is abnormal, and it has been suggested that a disease in ivhich all the sodium channels were affected would be nonviable (Peterson 1997). 

Abnormally high concentrations of sodium and chloride are found in sweat due to impaired reabsorption within the sweat duct from loss of CFTR channels. Patients are usually asymptomatic (other than a characteristic salty taste to the skin).2 In rare instances such as hot weather or excessive sweating during physical activity, patients may become dehydrated and experience symptoms of hyponatremia (nausea, headache, lethargy, and confusion). Similar CFTR defects are also seen in the salivary glands, manifested by increased saliva viscosity and impaired salivary function. 

In order for the battery to function, the lithium iodide must be able to transfer ions. Lil adopts the sodium chloride structure, and there are no open channels for ions to use. In fact, the cell operation is sustained by the Schottky defect population in the... 

Membrane-bound enzymes, particularly the ATPases involved in the ionic pumps for calcium, sodium and potassium, have been found to function abnormally in the brains of epileptic patients and animals. A reduction in Na+K+-ATPase activity has been reported in human focal epileptogenic tissue, but it is uncertain whether such changes are due to the disease itself or a reflection of drug treatment. Similar changes have, however, been reported in experimental animals following the localized application of alumina cream and in DBA/2 mice that exhibit sound-induced seizures a reduction in calcium-dependent ATPase has also been found in the brain of DBA/2 mice. Such findings are consistent with the hypothesis that a defect in ion channels may occur in epilepsy. 

A defective CFTR channel will disturb electrochemical gradients in both intestinal crypt cells and pancreatic epithelial cells, with a common end resutt, namely the inability to secrete water into the lumen. In crypt cells, chloride is normally transported to the lumen, drawing sodium ions across the tight junctions and creating an osmotic potential that in mrn draws water into the lumen (Figure 4.11). A defective CFTR wiU prevent the gradient forming and hence halt water movement to the lumen. 

Recently, Cl" channels have been discovered. These channels have no sequence relationship to the voltage-gated Na, and Ca channels. One such channel is involved in the disease, cystic fibrosis. In this disease, regulation of the channel is defective. The altered function of the channel in epithelia causes elevated levels of sodium and chloride ions in sweat and, through unknown processes, the accumulation of mucus in the respiratory tract and failure of exocrine secretion in glands, such as the pancreas. Blockage of airways leads to chronic lung infections that, with other effects of the Cl" transport deficiency, can be fatal. 

The major disease clearly linked with disordered sodium homeostasis, among other diseases, is hypertension, and this is observed in very small populations with genetic defects including glucocorticoid-responsive aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess (AME) (Anke 2002). Cystic fibrosis is another genetically determined defect in the chloride channels. This leads to the secretion of sweat with high NaCl concen-... 

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