Weizmann Institute scientists have discovered a new mechanism that enables fast and precise control of signals transmitted from nerve cells to muscle cells
The hero of the film (like any hero) is sitting quietly with his friends, when suddenly, without any warning, a life-threatening wave appears - a huge wave, a monster or a bloodthirsty criminal - forcing him to jump to his feet and escape for his life. In such cases his heart must speed up its beats drastically to pump enough blood to the muscles so that he can escape safely. How does the heart "shift" so quickly, from a relaxed rhythm to a frenzied pump? Since everyone knows the drama of sudden danger, this question is relevant to all of us, not just movie heroes.
In a study recently published in the scientific journal Cell, scientists from the Weizmann Institute of Science reported on a new mechanism they discovered, which enables the rapid and precise control of signals transmitted from nerve cells to muscle cells, such as the signals that control the heartbeat rate of the heart muscle. The findings of this study help explain the extraordinary precision of the control of signals in the heart and brain. The research was carried out by research student Adi Rowe in collaboration with Ayelet Cooper and Liora Gay-David, in the laboratory of Prof. Eitan Reuvani from the Department of Biological Chemistry.
To transmit electrical signals between nerve cells, or between a nerve cell and a muscle cell, ion channels open momentarily in the cell membrane - tiny tubes with the help of which the electrical activity in the cell is created - to allow the passage of charged ions into or out of the cell. The opening of the channels occurs according to the instruction of a nerve conductor (neurotransmitter). The neurotransmitter functions as a kind of chemical messenger, which binds to a receptor in the cell membrane and activates a molecule called G protein, which is found inside the cell. Protein G opens the ion channel by changing its structure - an action similar to releasing the tongue of the lock, allowing the door to open.
To prepare the cell to receive the next signal, the ion channel must of course close. This action does occur when the neurotransmitter is active for the duration of the short term. In this case, no more signal is sent from the cell membrane, and the G protein stops working - which causes the "lock tongue" to close. In cases where the neurotransmitter works for a long time, the cell has an additional mechanism that ensures that the ion channel does not remain open forever. This mechanism relies on an "internal auditor", an enzyme called GRK, which cancels the receptor's activity: it attaches a phosphorus molecule to the receptors, thus causing these receptors to enter the cell. As a result, they cannot respond to the arrival of the neurotransmitter, and do not cause the channels to open.
An example of the intervention of the "internal auditor" GRK is related to the long-term neurotransmitters such as morphine and other opiates, which are used as pain relievers. When these substances are given as drugs, they lose their effectiveness after a while because the GRK removes all G protein receptors from the cell membrane. In this way, the transmission of signals instructing the opening of the ion channels is actually stopped, and the pain relievers can no longer work. This is an example of a case where an essential mechanism for cellular communication becomes a disorder that prevents medical treatment. For this reason, it is recommended not to give opiates for a long time without a break, so that the patients do not lose their sensitivity to these drugs.
The control action performed by the GRK, that is, pulling the receptors into the cell, is a relatively slow process, which may last several hours. But what happens if the channel needs to be closed immediately? For example, in order to speed up the heart rate following an environmental change, the neurotransmitter that slows down the heart rate needs to be quickly braked - that is, the ion channel must be immediately closed - in order to free up space for the activity of another neurotransmitter, adrenaline, which speeds up the heartbeat. Scientists have known for some time that the channel can indeed be closed rapidly, even in the presence of a long-range neurotransmitter. But what causes the rapid closure?
In their new study, the institute's scientists found the answer. They discovered that the "visitor" GRK can put an end to the activity of the G protein through another and unknown mechanism, which works much faster than pulling the receptor into the cell. It turns out, that the GRK can simply rush towards the ion channel, and within seconds remove the G protein from there by itself. And once the G protein is removed, the ion channel closes.
To discover the mechanism, the scientists performed sophisticated experiments with nerve and muscle cells. They measured electrical currents passing through the cell membrane, followed the movement of proteins using fluorescent markers, and selectively disrupted the activity of certain molecules through genetic manipulations, in order to find out their role in the cell.
The new mechanism explains how it is possible to turn off electrical signals in the body quickly and accurately. This understanding sheds new light on the function of the ion channels in the entire body, but especially in the heart and brain, where the rapid control of the signals is essential. This is how the "auditor" GRK manages to quickly turn off the signal that slows down the heart rate, and prepares the muscle cells for the arrival of the adrenaline signal, which immediately speeds up the heart rate. In this way, the muscles are guaranteed a large amount of blood required for vigorous activity such as running - to ensure that the hero who is in danger of life will survive until the end of the film.
