Introduction of ion channels
When living cells continue to carry out metabolic activities, they must constantly exchange substances with the surrounding environment, and ion channels on the cell membrane are an important way to exchange such substances. It is known that most substances important to life are water-soluble, such as various ions, sugars, etc., which need to enter cells, and the water-soluble wastes produced in life activities also leave the cells, they come in and out by channels. These channels are ion channels on the cell membrane. Ion channels are made up of special proteins produced by cells. They are gathered and embedded in the cell membrane, and forming hydrophilic pores. These pores are the channels which water-soluble substances can quickly enter and exit the cells. These channels are the material basis for bioelectricity transport activities of cells such as nerves, muscles, and blood vessels. Ion channels are one of the cornerstones for living organisms to maintain normal function. Mediated bioelectrical signals play a key role in all life processes such as heartbeat, hormone secretion, signal transduction, cognitive memory and the like. Mutations in ion channels at the genetic level can lead to a variety of diseases including the nervous system, cardiovascular system, and endocrine system diseases. The regulation of vasoconstriction and diastolic activity also depends on the opening and closing of vascular ion channels. The blood vessels are generally divided into vascular smooth muscle cells and vascular endothelial cells. After receiving external stimuli on smooth muscle, various direct and indirect pathways can be induced to stimulate various kinds of pathways. With the opening and closing of ion channels, endothelial cells are able to release various factors to control and regulate the opening and closing of ion channels on the vascular smooth muscle cell membrane. Therefore, since the concept of ion channel has been proposed, the study of cardiac ion channel has become one of the hot spots in the field of heart disease.
The relationship of ion channels and cardiovascular
The ion channels are numerous and complex, and the Na+, K+ and Ca2+ channels are closely related to the heart. Many cardiovascular diseases are associated with abnormal ion channel function at some point or stage of their onset; similarly, many cardiovascular drugs are effective by correcting the abnormal function of certain ion channels.
Sodium ion channel
The cardiac sodium ion channel is composed of three subunits: α, β1 and β2, and the α subunit is its main functional group. The human SCN5A gene encodes a cardiac sodium channel alpha subunit. The alpha subunit consists of four homologous regions at the molecular level, each of which has six transmembrane helix segments. Activation of the cardiac sodium channel leads to a rapid influx of Na+, depolarization of the cardiomyocytes, and formation of phase 0 of the action potential. Changes in cardiac sodium channels directly affect the self-discipline, conductivity, and action potential duration of cardiomyocytes, leading to the occurrence of arrhythmias. In clinical studies, mutations in the SCN5A gene have been found to cause Brugada syndrome. The clinical manifestations of paroxysmal ventricular tachycardia or ventricular fibrillation often lead to sudden death during nighttime sleep, and the electrocardiogram presents symptoms such as right bundle branch block. The effect of related sodium channel inhibitors on the treatment of related conditions remains unclear.
There are three main calcium channels on the cell membrane: voltage-dependent calcium channel (VOC), receptor-operated calcium channel (ROC) and calcium-operated calcium channel (SOC). The opening of the ion channel of smooth muscle cells in the tube can change the change of calcium ion concentration in vascular cells and regulate the relaxation and contraction of vascular smooth muscle. The intracellular Ca2+ mainly comes from the extracellular Ca2+ into the cell through the calcium ion channel or into the cell from endoplasmic reticulum. So calcium channel is a very important in regulating vasodilation and contraction.
There are six types of VOCs on the membrane: T, L, N, P, Q, and R. L-type calcium ions are present on the blood vessels. The channel, at high voltages, the L-type calcium channel is easily activated. After the channel is opened, extracellular calcium will flow in a large amount, causing hyperpolarization, which causes the blood vessels to contract, and its Ca2+ influx lasts for a long time. The calcium channels of N, P, Q, and R types are distributed in nerve cells.
By binding the agonist to the corresponding receptor on the membrane, the receptor changes and ROC is opened. Unlike VOC, it does not change due to changes in membrane potential, and its opening is related to the formation of phosphoinositide.
It is a type of Ca2+ channel that is activated by Ca2+ clearing in the sarcoplasmic reticulum calcium pool and participates in various pathological and physiological processes, such as cell secretion, enzyme activity, cell cycle and apoptosis.
Potassium ion channel
There are four main potassium channels: voltage-activated potassium channels (Kv), calcium-activated potassium channels (Kca), adenosine triphosphate-sensitive potassium channels (KATP), and inward-rectifying potassium channels (KIR). The potassium ion channel regulates the potential on the smooth muscle cell membrane, thereby affecting the change of vascular tone. After the opening of the K+ channel on the vascular smooth muscle cell membrane, causing a large outflow of K+, and causing hyperpolarization of the cell membrane potential. The increase of K+ efflux causes the influx of Ca2+ to decrease, and the VOC is inactivated and closed, thereby causing vasodilation.
The influx of Ca2+ is the response of endothelial cells to stimulate factors. Ca2+ activates potassium channels, and compensate for the depolarization of the membrane potential under Ca2+ influx. The rapid outflow of K+, which leads to hyperpolarization of membranes, and Ca2+ continues to largely enter the cell. Kca has included a large-conductance calcium-activated potassium channel (BKca), a calcium-activated potassium channel (IKca), and a small-conductance calcium-activated potassium channel (SKca). Studies have shown that Kca has great physiological significance in the regulation of endogenous tonicity of resistance vessels. It is widely present in pulmonary artery smooth muscle cells (PASMCs). Kca channels can participate in the regulation of vascular tone by directly responding to changes in intracytoplasmic Ca2+. The BKca channel is dominant in most arteries, and inhibition of the BKca channel can depolarize the membrane and cause contraction.
KIR is only present in certain small-diameter cerebral blood vessels, submucosal arterioles and coronary artery smooth muscle, and KIR2 is the major KIR subtype. Under resting tension, strontium ions induce contraction of these blood vessels, and the KIR2 channel has high sensitivity to vasoconstriction and vasodilators, which in turn affect the resting membrane potential of the brain and coronary arteries.
In terms of molecular structure, the KATP channel is a heterologous octamer formed by the inward rectifier potassium channel Kir6x and ATP to form a box protein (SUR) at a ratio of 1:1. The Kir6x subunit is the target for ATP to inhibit this channel, and the selectivity of the KATP channel for K+ is also determined by it.
On certain vascular smooth muscles, Kv dominates in determining resting membrane potential and basal regulation. Furthermore, Kv channels rely on the regulation of agonist-induced protein kinase-dependent signaling pathways, so it has been found in studies that the use of protein kinase inhibitors can directly inhibit Kv channels.
In the function of vascular, various ion channels and vascular endothelial releasing factor regulate the function of vasoconstriction and relaxation of blood vessels, and study the relationship between ion channels and endothelial releasing factor on vascular smooth muscle, which is helpful for further study the ion channel on vascular smooth muscle. Studies have laid a solid foundation for the ion channel to become an important target for drugs to regulate vasodilation and contraction. It will be of great significance for the understanding and treatment of many related diseases and for the development of related drugs.