An Open- and Shut- Case

 

 

The hero, as heroes do, is relaxing with friends or enjoying a meal, when a mortal threat – a giant wave, a monster or a blood thirsty criminal – appears with no prior warning, compelling the hero to jump up and run for his life. As he does so, his heart must speed up its beat drastically within seconds, pumping extra blood to his muscles to ensure his safe escape. How can the heart “shift gears” so quickly, from beating at a leisurely pace to thumping frantically? The drama of sudden danger is familiar – not only to motion picture heroes – so this question is relevant to all of us.

 

To convey electric signals that transmit messages between nerve cells or from nerve cells to muscle cells, ion channels in the cell membrane – through which the cell’s electrical activity is generated – open up for a moment to allow the flow of charged ions into or out of the cell. In this particular case, the opening occurs when a neurotransmitter – a chemical messenger – binds to a receptor in the cell membrane, activating an intracellular molecule called the G protein. This protein then opens up the ion channel by altering its structure – an action akin to releasing a door latch, allowing the door to open.
 

To prepare the cell for receiving the next signal, it’s obvious that the ion channel must close again after a while. This indeed happens very soon if the neurotransmitter is short-lived: With no signal from the cell membrane, the G protein is deactivated, resulting in the closing of the “door latch.” But if the neurotransmitter is long-lived, the cell has an additional mechanism that makes sure the ion channel doesn’t stay open continuously. This mechanism involves an internal “controller,” an enzyme known as GRK, which cancels the G protein’s activity: GRK causes these receptors to be drawn inside the cell, which means that they no longer respond to the neurotransmitter and consequently no opening of the channel occurs.
 

One example of GRK controller activity has to do with such long-lived neurotransmitters as morphine and other opioids, commonly used as painkillers. When given as drugs, these neurotransmitters lose their effectiveness after a while because the GRK removes all the G-protein-linked receptors from the cell membranes, thereby preventing the generation of the signal for ion channel opening; these painkillers can then no longer exert their action. Thus a mechanism so vital to normal cellular communication becomes an impediment to therapy. For this reason, it is recommended that opioids not be given continuously for too long, to prevent the patient losing sensitivity to these drugs.
 

This control function of GRK – drawing the receptors into the cell – is a relatively lengthy process that can take hours. But what happens if the opening and closing of ion channels needs to be controlled much more quickly? To adjust the heartbeat to a sudden change in the environment, the neurotransmitter that slows down the heart rate must be instantly turned off, closing down the ion channel to make room for adrenalin action, which makes the heart beat faster. In fact, scientists have known for some time that the ion channel can indeed shut down very quickly, even in the presence of a long-lived neurotransmitter. What causes this rapid shutdown?

 

 

In their new study, Weizmann Institutes scientists have found the answer. They discovered that the GRK controller can terminate the action of the G protein in a previously unknown manner – one that is much faster than the lengthy drawing of the receptor into the cell. It turns out that within seconds, the GRK can simply rush to the door-latch control mechanism and, rather than bothering to relocate receptors, simply remove the G protein itself. Once the G protein has been pushed away from the “door handle,” the ion channel closes down.
 

To reveal this mechanism, the Weizmann team conducted elaborate studies using nerve and heart muscle cells. These studies involved measuring electric currents passed through the cell membrane, tracing the movement of proteins by labeling them with fluorescent markers and selectively disrupting selected molecules by genetic manipulation in order to elucidate their function.
 

The newly discovered mechanism helps explain how electric signals in the body can be turned off rapidly and precisely. This new understanding sheds fresh light on the functioning of ion channels throughout the body but particularly in the heart and brain, where rapid signal regulation is crucial. Thus, in an instant, the GRK controller can turn off the slow, steady heartbeat signal to make way for the adrenalin signal, which immediately makes the heart beat faster. In this way, the body’s muscles are quickly provided with the massive supply of blood needed for intensive activity, such as running – ensuring that the hero faced with sudden danger will survive until the end of the film.