That
flutter in your heart may have more to do with the movement of sodium
ions than the glance of a certain someone across a crowded room.
Using
the Canadian Light Source synchrotron, researchers from the University
of British Columbia have revealed, for the first time, one of the
molecular mechanisms that regulates the beating of heart cells by
controlling the movement of sodium in out of the cells—and what calcium
has to do with it. The findings, published Feb. 14 in the Proceedings of the National Academy of Sciences,
sheds new light on this crucial physiological process while revealing
the root cause and possible treatment targets of two potentially
life-threatening cardiac arrhythmia conditions.
The
contraction and relaxation of heart muscle cells depend on minute but
finely regulated electrical impulses that are created when charged
atoms—or ions—of metals such as sodium, potassium and calcium pass
through complex molecular channels inside and between cells. Irregular
heartbeats, referred to medically as arrhythmias, can happen when these
channels leak or otherwise malfunction. Professors Filip van Petegem and
Christopher Ahern, members of UBC’s Cardiovascular Research Group, used
the CLS to determine the molecular structure of a part of the channel
that controls the flow of sodium to cells in the heart, as well as in
other electrically-excitable cells such as in the nervous system.
“The
heart is an electrical organ that depends on precise electrical signals
to contract [and pump blood]” explains van Petegem. “It is crucial for
heart rate that the signalling, controlled by the movement of sodium, be
exact. So the entry of sodium into the cell is tightly regulated.”
The
sodium channel that passes through the outer membrane of heart cells is
actually a huge, intertwined four-part molecule. The teams of Van
Petegem and Ahern chose a section of the molecule that appeared to
regulate the closing of the channel by forming a plug, thus stopping
sodium from getting through.
The
researchers were surprised to discover that a protein called calmodulin
binds to the sodium channel, keeping it open by preventing the plug
from forming. Calcium ions, in turn, regulate the connection between the
protein and the channel: calcium ions cause the protein to hook up to
the channel, keeping it open and letting sodium through.
Problems
occur with the system when genetic mutations change the shape of the
channel at the site where the protein binds, affecting how well the
channel can open and close. The result—the flow of sodium into the
muscle cells is disrupted and the heart does not beat regularly.
The
scientists have been able to identify mutations in the site that lead
to two different kinds of heart arrhythmia: Brugada Syndrome and Long
Q-T type 3, so-called from the tell-tale trace doctors see on the ECG of
patients suffering from the problem. Brugada syndrome is considered to
be caused by not enough sodium getting into cells, while long Q-T is the
result of too much sodium.
The
results of the study could pave the way for the development of new
drugs that can shore up how the calmodulin protein binds to the sodium
channel, effectively treating both conditions as well as other
arrhythmias.
“It’s
really a very elegant mechanism,” notes van Petegem. “Many channels are
regulated by calmodulin but not in such a simple way.”
Crystallographic basis for calcium regulation of sodium channels
