Structure reveals mechanism behind periodic paralysis

The results suggest possible drug designs that could provide relief to patients with a genetic disorder that causes them to be overcome suddenly with profound muscle weakness.

A rare genetic disorder called hypokalemic periodic paralysis (hypoPP) causes sudden, profound muscle weakness in people who occasionally exhibit low levels of potassium in their blood, or hypokalemia. When a patient is hypokalemic, hypoPP affects the function of the muscles responsible for skeletal movement. The disease has been known to stem from mutations in certain membrane proteins that channel and regulate the flow of sodium into cells. Exactly how the mutation affects the proteins’ function, however, was not known.

In earlier work, researchers from the Catterall Lab at the University of Washington had solved the structure of a sodium channel called NavAb from a prokaryote (single-celled organism). As a next step, the group decided to see if NavAb could serve as a model for studying the mutations that cause hypoPP in humans (eukaryotes), with the goal of finding a way to prevent or treat this disorder.

A leak in the pipe?

In a resting state, muscle-cell membranes keep potassium ions and sodium ions separated, inside and outside the cell, respectively, creating a voltage across the membrane. A chemical signal from a nerve cell sets off a cascade of events that results in sodium ions flowing into the cell, changing the membrane potential and and ultimately triggering muscle contraction.

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Image: Three states of the voltage-sensing domain (VSD) of a membrane-channel protein. In the normal state, the water-accessible space (magenta) does not extend through the channel, preventing sodium (gray spheres) from passing through. In the disease state, a clear passage allows sodium to leak through, resulting in muscle paralysis. In the “rescued” state, the binding of guanidinium (blue and yellow spheres) effectively closes the channel and blocks sodium leakage. The red sphere represents the location of the disease-causing mutation. The side-chain sticks represent the voltage sensors of the sodium channel.