You are studying a new virus whose effects include loss of motor control in all

Question

You are studying a new virus whose effects include loss of motor control in all limbs due to an imbalance of intracellular potassium ions. You discover that this is due to viral induced depolarization of nerve membranes, resulting in constitutive activation of the voltage-gated K+ channel. You begin to design drugs that will stop the passage of K+ ions through this channel. Based on your mechanistic knowledge of the physical characteristics and mode of regulation of the voltage-gated K+ channel, describe two strategies whereby new drugs could inhibit K+ ion flow through this channel. (6 points)

Explanation / Answer

Voltage gated K channels allow the passage of K ions and are sensitive to changes in the membrane voltage which leads to spreading of the action potential. To look for targets we need to know the structure of the voltage gated K channel. Typically, vertebrate voltage-gated K+ channels are tetramers of four identical subunits arranged as a ring, each contributing to the wall of the trans-membrane K+ pore. Thus, first of all this pore has a defined size and shape for K channel and this can be used by inhibitor to block the movement of K ion.

When the channel opens their is a conformational change in the Voltage sensor domains (VSD) which result in the transfer of charge. There are charged residues like Arginine present in these VSDs in a typical three dimensional conformation. These specific VSD domains can be used as bloking sites by inhibitors to inhibit the charge transfer and hence the spreading of action potential.

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