How is the heartbeat signal transmitted?

Arrhythmia, as a common cardiovascular disease, mostly occurs in the elderly
.
However, with the change of lifestyle, the risk of illness among the young and middle-aged population is also increasing

When our heart beats, the contraction and relaxation of cardiomyocytes are controlled by a tiny but very fine electrical signal.
There are sodium, potassium, and calcium plasma channels inside and between cells.
When these channels fail, It will cause the heart to beat irregularly
.

Recently, the Institute of Physics of the Chinese Academy of Sciences and the University of Washington in the United States published a study in Cell, which analyzed the structure of the open cryo-electron microscope of the sodium channel mutant Na _V 1.
5/QQQ, and revealed the anti-arrhythmic drug Propa The binding site of ketone (Propafenone) and open sodium channel
.
This will provide a structural basis for the development of new antiarrhythmic drugs

The heart beats, cannot do without Na _v 1.
5

Voltage-gated ion channels play an important role in numerous physiological processes in the body, such as gene expression, transmission of nerve signals, muscle contraction, nerve degenerative diseases, heart disease, mental illness and so on
.
Ion channel proteins are currently the second largest drug therapy target after GPCR (G protein coupled receptor)

Sodium ions are involved in physiological processes such as heartbeat, nervous system regulation, and muscle contraction
.
The voltage-gated sodium channel (Na _v ) protein family includes 9 members, namely Na _v 1.

When changes in membrane potential of cardiomyocytes occurs, of Na _V for 1.
5 will be immediately activated, the shutter open channel, so as of Na ⁺ smoothly into the outer membrane from the cell membrane, this time, of Na _V is in the open state
.
When a certain amount of Na ⁺ enters the membrane, a new action potential is generated and the cardiomyocytes contract

In recent years, Jiang Daohua, a distinguished researcher of the Institute of Physics, Chinese Academy of Sciences, has been committed to analyzing the structure of Na _v 1.
5 and its interaction with clinical drug molecules.
In 2020, he was still a postdoctoral fellow at the University of Washington in the United States and worked with his collaborators to analyze The structure of cardiomyocytes Na _V 1.
5 in the inactive state
.

Capture 5 milliseconds of state

Although there are antiarrhythmic drugs such as lidocaine, flecainide and quinidine, they have been used clinically for more than ten years, and their effects are relatively significant
.
But a key issue is that these drugs have side effects

"As the Na _v similarity nine members of the sequence, when the drugs act on the Na _v 1.
5, they often also affect the other members, which inevitably brings nausea, fainting and other side effects
.
Therefore, we hope to design The development of small drug molecules with targeted selectivity only works on Na _v 1.

It is understood that for Na _v 1.
5 in the heart, the open state after each activation only lasts for about 5 milliseconds, which is a very difficult state to capture
.

How can we capture the dynamics of this moment and show them?

The research results show that when Nav1.
5 is closed, a domain called IFM motif is needed to help.
IFM motif is like a plug, blocking the channel to prevent the transmission of the insulator
.

"Using the method of point mutation, we mutated the IFM motif into the amino acid QQQ.
After the formation of the IFM/QQQ mutant, it cannot function as a'plug'.
In this way, Na _v 1.
5 can always remain open
.
" Jiang Daohua said

But soon, the researchers encountered a new problem: Na _v has been kept open, and Na ⁺ continuously enters the cell from outside the membrane.
Before the structure is purified, the cell will be overconcentrated by the Na ⁺ concentration.
High to death
.

"Here is the use of small anti-arrhythmic drugs.
Through repeated screening, we found that when propafenone is used as a blocking agent on Na _v 1.
5, it can effectively alleviate cytotoxicity
.
" Jiang Daohua said
.

He said, "Later, we used cryo-electron microscopy to analyze the structure of the open sodium channel with a resolution of 3.
4 angstroms, and revealed the structural basis for the rapid opening, rapid inactivation and open-state blockade of sodium channels at the atomic level
.
"

Facilitate the development of anti-arrhythmic drugs

The three-dimensional reconstruction image shows that the four subunits of Na _v 1.
5 overlap each other to form a central channel that is approximately cuboid.
When it is in an open state, the four subunits move outwards by 0.
6 nanometers respectively, that is, one The hair is about 1/80000
.
When the channel is closed, the four subunits return to their original positions
.

"The sodium ion channel is really very delicate.
It only needs a small movement to switch from the open state to the closed state
.
" Jiang Daohua said, we also found that the antiarrhythmic drug propafenone can pass through the open state.
The activation opening of Na _V 1.
5 reaches the high-affinity binding site of the central channel, specifically blocking Na _V 1.
5
.

Later electrophysiological experiments further confirmed that propafenone is an open state blocker
.

"This research uses clever design to freeze the channel in the'open state' state, and uses structural biology to reveal the structural characteristics of the open state of eukaryotic sodium ion channels for the first time
.
This work not only deepens our understanding of Including the understanding of the gating mechanism of the _Nav channel, and the open state structure will also greatly assist the research and development of drugs related to the sodium ion channel
.
" said Zhao Yan, a researcher at the Institute of Biophysics, Chinese Academy of Sciences
.
(Source: Liu Runan, China Science News)

Related paper information: https://doi.
org/10.
1016/j.
cell.
2021.
08.
021