- Number 325 |
- November 22, 2010
X-Rays offer first detailed look at hotspots for calcium-related disease
High-resolution images of the
ryanodine receptor reveal the
locations of more than 50
mutations in a disease
"hotspot.” (Image courtesy
Filip Van Petegem, University
of British Columbia.)
Calcium regulates many critical processes within the body, including muscle contraction, the heartbeat, and the release of hormones. But too much calcium can be a bad thing. In excess, it can lead to a host of diseases, such as severe muscle weakness or sudden cardiac death.
Now, using intense X-rays from the Stanford Synchrotron Radiation Lightsource at DOE's SLAC National Accelerator Laboratory, researchers have determined the detailed structure of a key part of the ryanodine receptor, a protein associated with calcium-related disease. Their results pinpoint the locations of more than 50 mutations along the receptor.
"Until now, no one could tell where these disease mutations were or what they were doing,” said principal investigator Filip Van Petegem of the University of British Columbia in Vancouver. Previous studies indicated that mutations cluster in three “hotspots” along the receptor, but it remained unclear exactly how they contributed to disease.
In a study recently published in Nature, Van Petegem and his group describe the structure of one of these hotspots and predict how the mutations might cause the receptor to malfunction.
The ryanodine receptor is made up of more than 20,000 molecules called amino acids. The group found 57 mutations in a string of about 560 amino acids. In 56 cases, the mutations involved a change in a single amino acid, while the last one involved a deletion of 35 amino acids.
The receptor controls the release of calcium ions within skeletal-muscle and heart-muscle cells. In the heart, it is stimulated to open about once a second when the body is at rest, sending regular pulses of calcium into the rest of the cell. In skeletal muscles, the timing of the pulses is determined by how often the muscles contract. Mutations can disrupt this process by causing the receptor to open either earlier or more easily than it should.
This premature release of calcium produces extra electrical signals within the cells. In skeletal muscle, this can lead to fatal rises in body temperature under certain anesthetics, or the failure of major muscles. In cardiac muscle it can trigger an arrhythmia, resulting in sudden cardiac death. It is estimated that as many as one in 10,000 may be at risk for disease.
"These mutations could be a very promising therapeutic target,” Van Petegem said. Future studies will map out other receptor hotspots and use the detailed information to better understand the complex functions of the protein. —Lauren Rugani
[Melinda Lee, 650.926.8547,