A human genetic disease called periodic paralysis is caused by defects in the vo

Question

A human genetic disease called periodic paralysis is caused by defects in the voltage-gated Na+ channel that is expressed in skeletal muscle. These defective channels sometimes fail to inactivate after they are opened by a depolarizing graded potential.
a) How would this defect affect the changes in membrane potential observed in skeletal muscle during an action potential?
b) Why would this defect cause paralysis? Explain.
c) In some patients, the paralysis is most often observed following a period of prolonged exercise. In these patients, the channel fails to inactive only when extracellular K+ levels are higher than normal (the channel inactivates properly when extracellular K+ is normal). How might exercise result in high concentrations of extracellular K+?

Explanation / Answer

a and b) The functions of the voltage-gated Na+ channel include voltage-sensitive gating, inactivation, and ion selectivity.

There are 2 gates (activation and inactivation) in sodium channel and exist in 3 states. During rest with the polarised membrane, the gate activation gets closed and the inactivation gate opens. But during depolarization, vice versa that allows sodium ions to pass through the ion channel and exposes a docking site for the inactivation gate. With this continued depolarization, causes the channel to enter the fast-inactivation state. Further, this inactivation of the channel makes membrane re-polarized, resulting in a return to the resting state with the activation gate closed and the inactivation gate opened. These inactivation processes occur in mammalian skeletal muscle are terminating the action potential with fast inactivation on a millisecond time scale and slow inactivation takes seconds to minutes and this regulates the population of excitable sodium channels. In Periodic paralysis, a gain of function happens in mutant channel results in increased sodium current leading excessively depolarising the affected muscle. If more depolarization occurs, it causes weakness or paralysis.

c) Insulin and catecholamines are released during exercise and by high carbohydrate food. This increases concentrations of extracellular K+. During exercise, repeated action potential and skeletal muscle contraction result in the release of a considerable amount of potassium into the extracellular space. This enters the systemic circulation, which makes the venous potassium concentration becomes 7-fold higher than the pre-exercise level after 5 minutes of cycling exercise.

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