Researchers have advanced their understanding of how an altered cell membrane protein causes a rare genetic disorder called hypokalemic periodic paralysis. Individuals with the autosomal dominant disorder experience sudden attacks of overwhelming muscle weakness or paralysis when blood potassium levels fall below a certain threshold. The study was published by researchers at the University of Washington School of Medicine in Nature.
"Our results reveal the mechanisms of periodic paralysis at the atomic level and suggest designs for drugs that may prevent this ion leak and provide relief to these patients," said William A. Catterall, a professor of pharmacology at the UW School of Medicine who led the research.
Sodium-potassium pumps move sodium ions out of the cell in exchange for potassium ions in order to maintain a charge difference, or voltage, across cell membranes of resting muscle cells. This ion channel protein keeps the concentration of potassium higher inside the cell and the concentration of sodium higher outside the cell. The charge difference, approximately -90 millivolts, is the transmembrane voltage that drives the cell membrane machinery. The muscle contraction process is initiated by a nerve that opens some ion channels allowing sodium ions to flow into the cell which lowers the transmembrane voltage. The voltage change is detected by voltage-gated sodium channels which are triggered to open allowing even more sodium ions to flow into the cell. The membrane potential change generates an “action potential” which triggers muscle contraction.
The voltage sensor is the part of the voltage-gated sodium channel that detects and responds to membrane potential changes. It changes its molecular shape causing the channel to open and allow sodium ions to pass into the cell. Individuals with hypokalemic periodic paralysis have a mutation in the sensor portion part of the voltage-gated sodium channel that detects voltage change. The researchers used X-ray crystallography to determine the structures of both normal and mutant voltage sensor proteins down to the atom. The structures show that there is a small hole in the mutant form that allowed sodium ions to continuously leak out.
"This leak causes sustained membrane depolarization and action potential failure, thereby paralyzing the muscle," Catterall said.
The study also found that compounds with a guanidinium chemical group have the ability to block the hole which stops sodium from leaking and keeps the voltage sensor functioning properly.
"Our high-resolution structural models may provide templates for drugs that mimic the effect of guanidinium, block the gating pore current, and could perhaps prevent or treat periodic paralysis," Catterall said.
Image: The voltage sensor has two cavities (purple) that do not connect. Mutations (red) linked to periodic paralysis allow them to join, thereby creating a pore through which ions can leak. Compounds (blue and yellow) that block the pore could treat the condition. Image coutesy of Ning Zheng & Catterall labs/UWMedicine.