Sodium channel point mutation

Sodium Channel Point Mutations Associated with Pyrethroid Resistance in the Head Louse, Pediculus humanus capitis... 

In the Long QT Syndrome (LQTS), the repolarization phase of the cardiac muscle is delayed, rendering the heart vulnerable to an arrhythmia known as torsade de pointes. LQTS is associated with five genes encoding ion channels. LQTS type 3 (LQT3) results from mutations of Nav1.5, which cause persistent sodium cunent. In contrast, sodium channel mutations associated with Biugada syndrome reduce the expression level of cardiac sodium channels. 

The primary sequences of important channel peptides, such as the nicotinic acetylcholine receptors, and sodium, potassium, and calcium channels, have been determined by the innovative work of the late professor Numa and his group. " Thereafter, various structural models on the basis of empirical as well as molecular mechanics or molecular dynamics calculations were proposed " and tested by specific point mutation studies. 

He, H., Chen, A.C., Davey, R.B., Ivie, G.W., and George, J.E., Identification of a point mutation in the para-type sodium channel gene from a pyrethroid resistant cattle tick, Biochem. Biophys. Res. Commun., 261, 558,1999. 

Naturally Occurring Point Mutations in the Sodium Channel Gene Responsible for Knockdown Resistance to Pyrethroids. 

Several point mutations in the sodium channel gene are associated with kdr and kdr-type resistance to pyrethroids in agriculturally or medically important arthropod species. The most common mutation is the leucine (L) to phenylalanine (F) or histidine (H) or serine... 

The target biomolecules for DDT and the pyrethroids are the sodium channels in the axon. One very common type of resistance is the so-called knockdown resistance, or kdr resistance. In this case one or more amino acids have been changed due to point mutation so that DDT or pyrethroids do not bind. Whereas houseflies that are resistant due to the presence of the DDT dehydrochlorinase type of glutathione transferase will be paralyzed by DDT, it is found that when DDT has been detoxicated, the flies wake up and... 

Genetic analysis and biochemical studies have shown that kdr resistance is linked to one of the building blocks of the sodium channels in the axon (the gene for the so-called a-subunit). The gene has been sequenced in R-and S-flies. The substitution of a leucine residue with a phenylalanine residue makes the difference. Equivalent mutations have been found in pyre-throid-resistant strains of several other insect species. Two point mutations in the a-subunit of the sodium channels are associated with super-kdr resistance. Such mutations have been detected in the housefly, horn fly, diamond moth, and body louse. It may cause several hundred-fold resistance. It is interesting to note that if knockdown, and not death, is used as the endpoint, the resistance level is much higher. 

Potassium aggravated myotinia (PAM) SCN4A (skeletal muscle channel) 6 point mutations in regions associated with inactivation Slowed decay of transient sodium current... 

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