Tinkering with the CAR
Michael and his colleagues have been interested in CAR because it is a component of structures called tight junctions which tie cardiac cells together. The heart beats rhythmically because its cells are bound to each other in a way that allows them to pass along electrical signals. There are four types of cell junctions; defects in the other three are known to cause cardiac arrhythmia and death.
Until now, tight junction proteins had not been linked to arrhythmia. But infections by the coxsackie B virus are often followed by cardiac damage, which suggested that CAR might be involved. One way to find out would be to delete the CAR gene in mice – a technique that removes the molecule from an animal’s cells. Comparing such “knockout” mice with their healthy counterparts often reveals a gene’s functions and its contributions to disease.
The most basic method of knocking out genes removes a molecule from all of a mouse’s cells for its entire lifetime. But this can’t be done with many molecules, including CAR, because they have roles during embryonic development and cause mice to die before birth. Michael’s lab used an alternative method called a conditional knockout to remove the molecule only in the mature heart, producing a strain of mouse that could be used to investigate CAR’s functions in adult animals.
A study headed by PhD student Ulrike Lisewski revealed that CAR helps transmit electrical signals between cells to coordinate the pumping of the heart. Without CAR the rhythm was lost. Ulrike and her colleagues traced the problem to a structure in the heart called the atrioventricular (AV) node. This tissue is an important conduit of signals that organize a rhythmic pulse. Looking at cardiomyocytes under the microscope, the scientists saw that without CAR, other membrane proteins were disturbed. These proteins, called connexins, act as a channel that let charged molecules pass the cell membrane. This process regulates the production and timing of electric charges. Usually many copies of connexins are clustered together on the surface of AV cells. But cells without CAR had fewer copies of connexins, and they were spread loosely along the surface. The scientists believe that CAR normally holds them in place. Scattered connexin molecules might not be able to work together to coordinate signals.
A virus that interfered with CAR might have the same types of effects, but scientists have disagreed about why the coxsackie virus causes heart damage. This is another interest of the lab and is addressed in a second study by Yu Shi, an MD and postdoctoral fellow in Michael’s group, which will be published in the next few weeks.
The work suggests that CAR may be a key to treating heart damage. Researchers have already tried to use CAR to block coxsackie infections; one approach, for example, has been to insert the molecule into blood cells which lure the virus away from the heart and capture it. So far the results have been inconsistent. The new work reemphasizes CAR’s importance as a potential target for therapies, Michael says. But any strategy that changes its behavior will have to keep in mind the protein’s roles in the healthy heart. The search for new treatments must go hand-in-hand with acquiring a deep understanding of fundamental processes in cells.
Highlight Reference:
Lisewski U, Shi Y, Wrackmeyer U, Fischer R, Chen C, Schirdewan A, Jüttner R, Rathjen F, Poller W, Radke MH, Gotthardt M. The tight junction protein CAR regulates cardiac conduction and cell-cell communication. J Exp Med. 2008 Sep 29;205(10):2369-79. Epub 2008 Sep 15.
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