What Is a Sodium Channel Blocker?

Ion channels of biomembrane are channels for the passive transport of various inorganic ions across the membrane. There are two modes of transmembrane transport of biological ions for inorganic ions: passive transport (cis ion concentration gradient) and active transport (reverse ion concentration gradient). The path of passive transportation is called ion channel, and the ion carrier of active transportation is called ion pump. Biofilm's permeability to ions is closely related to various life activities. For example, the occurrence of sensory potentials, neural excitation and conduction and the central nervous system's regulatory functions, cardiac pulsation, smooth muscle peristalsis, skeletal muscle contraction, hormone secretion, formation of transmembrane proton gradients during photosynthesis and oxidative phosphorylation.

Biofilm ion channel

Ion channels of biomembrane are various

Changes in the biofilm's permeability to ions have been discovered in the study of bioelectricity generation mechanisms. In 1902 J. Bernstein proposed the neural cell membrane pair in his membrane doctrine

Research on the structure and function of ion channels requires comprehensive application of various technologies, including: voltage and current clamping technology, single-channel current recording technology, channel protein separation, purification and other biochemical technologies, artificial membrane ion channel reconstruction technology, channel pharmacology, genes Restructuring technology and some physical and chemical technologies.

Voltage clamping technology

In general, the change in membrane permeability to certain ions is

Ion channels can be divided into two types according to their activation methods: one is voltage-activated channels, that is, the opening of channels is controlled by membrane potentials, such as Na ⁺ , Ca ²⁺ , Cl ^- and some types of K ⁺ channels; The other is chemically activated channels, that is, channels that are activated by the interaction of chemicals with receptors on the membrane, such as Ach receptor channels, amino acid receptor channels, Ca ²⁺ activated K ⁺ channels, and the like.

Sodium channel

Among various biological materials, Na ⁺ channels related to electrical excitation have similar basic characteristics. The channel activation time constant is less than 1 millisecond, the deactivation time constant is several milliseconds, and the inversion potential of Na ⁺ current is about +55 millivolts. Single-channel current records show that Na ⁺ single-channel conductance is 4-20 pS, with an average open life of several milliseconds.

According to the different effects of some drugs and toxins on Na ⁺ channel function, it can be divided into 4 types:

Channel blockers, such as tetrodotoxin (TTX),

Molecular conformation and gating dynamics

The leading edge of ion channel research is trying to reveal the relationship between the spatial conformation, conformational changes and channel gating dynamics of channel proteins at the molecular level.

N-AchR channel

The molecular weight of the receptor protein has been determined to be 250,000, and its entire amino acid sequence has been determined. It has been confirmed that the receptor channel consists of five subunits, , , and . These four subunits have similar amino acid sequences, but only The subunit has a specific binding site for -BGTX. A conformational model is: each of the five subunits has several -helical transmembrane arrays, which together form a five-lobed protein complex. The two -subunits are hydrophilic ion channels with a channel opening of about 25 angstroms and a middle It is a narrow pore channel of 6 to 7 angstroms in which side chains of negatively charged amino acid residues are arranged. When two Ach molecules are bound to specific sites of two subunits, they cause local conformational changes and open the channel.

Sodium channel

The molecular weight of the sodium channel protein isolated from the electric eel plate is 208321, which is a polypeptide sequence composed of 1820 amino acids. It can be divided into 4 similar segments, each of which has a relatively concentrated positive and negative charge. Amino acid sequence segments. The common feature of various sodium channel conformation models is that the channel is composed of multiple alpha-helix transmembrane arrays. The inner side of the channel should be rich in polar amino acid residue side chains. The control part of each channel is controlled by ion selective filters and activation gates It consists of three parts, the inactivating gate, and its entity is a polar group of the amino acid side chain. When the membrane potential changes, the electric field induces the movement of polar groups, causing the local conformation of the channel to change, causing the channel to open, inactivate, or close, and generate a gated current. Regarding the transition between the closed, activated, and inactive states, there are two viewpoints: one considers that the channel must be activated from the closed state before it can be converted to the inactive state (coupling mode), and the other is that from the closed state Can be directly converted to the inactive state (non-coupling mode), currently uncoupling mode is supported by more experimental facts.

Ion channel characteristics

1. Selectivity: refers to the characteristics of one channel allowing certain ions to pass preferentially, while others cannot easily pass through the channel. For example, when sodium channels are open, sodium ions can pass, but potassium ions cannot pass.

2. Switchability: There are two states of the ion channel, namely the open and closed states. In most cases, ion channels are closed and open only under certain conditions. The process of changing the channel from closed to open is called activation, and the process of changing from open to closed is called inactivation. The channel opening and activation process has a certain rate, which is usually very fast and is calculated in milliseconds (ms).

Classification of ion channels

The opening and closing of ion channels is called gated. According to different gating mechanisms, ion channels are divided into three categories:

Voltage-gated, also known as voltage-dependent or voltage-sensitive ion channels: open and close due to changes in membrane potential, named after the most easily passed ions, such as four main types of potassium, sodium, calcium, and chloride channels, each There are several subtypes.

Ligand-gated, also known as chemically-gated ion channels. It is opened by the binding of a transmitter to a binding site on a channel protein receptor molecule. It is named after a transmitter receptor, such as an acetylcholine receptor channel, a glutamate receptor channel, an aspartate receptor channel, and other non-selective cations. Channels are opened by ligands acting on the corresponding receptors, while allowing sodium, calcium, or potassium to pass through.

(3) Mechanical gating, also known as mechanically sensitive ion channels: It is a type of channel that senses changes in cell membrane surface and realizes the transduction of extracellular mechanical signals into cells. It is divided into ion-selective and non-ion-selective according to permeability. Channels are classified into tension-activated and tension-inactivated ion channels according to their functional effects.

In addition, there are organelle ion channels, such as voltage-dependent anion channels that are widely distributed on the outer membrane of mammalian cells' mitochondria, and are located on the sarcoplasmic reticulum or endoplasmic reticulum of organelles, receptor channels and receptor channels on the membrane.

Voltage-gated calcium channels (VGC) are divided into four subtypes: L-type (Long-lasting), N-type (No-Long lasting, non-tsansient), T-type (Transient), and P / Q.

L-shaped channels: large conductance, slow inactivation, long duration, need strong depolarization to activate, are expressed in various tissues such as cardiovascular, endocrine and nerve, participate in electro-constriction coupling and regulate metabolism.

T-shaped channel: small conductance, fast inactivation, and weak depolarizing current can be activated, it is mainly distributed in the heart and vascular smooth muscle, triggering pacing electrical activity.

N-type channel: fast inactivation, requiring strong depolarizing current activation, currently only found in neural tissues, mainly triggering the release of sympathetic neurotransmitters.

P / Q channel: The same 1 subunit (1A) is collectively called the P / Q type calcium channel. P / Q-type calcium channels play an important role in neurotransmitter release.

Potassium channel: A protein complex that is widely available on the cell membrane through which potassium ions selectively pass, forming a large family of channels in structure and function. There are four basic types of potassium channels: voltage-gated potassium channels (KV), calcium-activated potassium channels (KCa), and adenosine triphosphate-sensitive potassium channels (ATP-Sensitive K + Channels, KATP).

Voltage-gated potassium channels are further divided into: Inward rectifier K + Channds (Kir), delayed outward rectifier potassium channels, and transient outward potassium channels.

Physiological function of ion channel

Increase intracellular calcium concentration, which triggers a series of physiological effects such as muscle contraction, cell excitement, glandular secretion, opening and closing of calcium-dependent ion channels, activation of protein kinases, and regulation of gene expression.

In excitatory cells such as nerves and muscles, sodium and calcium channels mainly regulate depolarization, and potassium mainly regulates repolarization and maintains resting potential, which determines the excitability, refractory, and conductivity of cells.

(3) Regulation of vasomotor smooth muscle contraction, which includes potassium, calcium, chloride channels and some non-selective cation channels.

is involved in synaptic transmission.

Maintain normal cell volume. In a hypertonic environment, ion channels and transport systems are activated to allow sodium, chlorine, and water to enter the cell to regulate cell volume increase. In a hypotonic environment, sodium, chlorine, and water flow out of the cell to regulate cell volume reduction.

Ion channel disease

When the gene encoding the ion channel subunit is mutated / abnormally expressed or a pathological endogenous substance targeted to the channel appears in the body, the function of the channel is weakened or enhanced to varying degrees, resulting in disturbance of the overall physiological function of the body, and some Congenital and acquired diseases.

Can be divided into congenital ion channel disease (genetic channel disease) and acquired ion channel disease (acquired channel disease), of which the latter can be caused by both abnormal gene expression and the appearance of antibodies and other substances.

According to the type of the channel, it can be divided into voltage-gated channelopat hy and ligand-gated channelopathy. The latter is also a kind of "receptor diseases".

According to the changes of ion channel function, it can be divided into: functional gain ion channel disease and impaired ion channel disease, etc .;

According to the system involved in ion channel disease, it can be divided into: neuromuscular system ion channel disease (such as BFNC (benign familial neonatal convulsions) caused by potassium channel mutation), cardiovascular system ion channel disease (such as long QT syndrome), urinary Systemic ion channel diseases (such as Bartter syndrome), respiratory ion channel diseases (such as pulmonary cystic fibrosis, etc.).

1. Potassium channel disease: Potassium channels play an important role in the important signal transduction of all excitable and non-excitable cells. Its family members are involved in regulating neurotransmitter release, heart rate, insulin secretion, nerve cell secretion, and epithelial cells. Electrical conduction, skeletal muscle contraction, and cell volume play important roles. Potassium channel diseases that have been discovered include benign familial neonatal convulsions, type 1 paroxysmal ataxia, paroxysmal choreography with paroxysmal ataxia, epilepsy, and long QT syndrome.

2. Sodium channel disease: Sodium ion channels play an important role in the initial stage of action potentials of most excitatory cells. Sodium channel diseases have been found to have periodic hyperparalysis of high potassium, periodic paralysis of normal blood potassium, and congenital muscle weakness Wait.

3. Calcium channel disease Calcium ion channels are widely present in different types of tissue cells of the body, and participate in the physiological processes of nervous, muscle, secretion, and reproductive systems. Calcium channel diseases that have been found include familial hemiplegic migraine, hypokalemic periodic paralysis, ataxia, and myasthenic syndrome.

4. Chloride channel disease: Chloride ion channels are widely distributed in the body's excitatory cells and non-excitable cell membranes and the plasma membranes of organelles such as lysosomes, mitochondria, and endoplasmic reticulum, which regulate cell excitability, transepithelial substance transport, and cells. Volume regulation and organelle acidification play an important role. Chloride channel diseases that have been discovered include congenital myotonia, recessive hereditary systemic myotonia, cystic fibrosis, and hereditary kidney stones.

Disease ion channel changes

The change of ion channels in the disease refers to the change in the number, function and even structure of one or several ion channels caused by a certain disease or drug.

Such as Alzheimer's disease (AD): A large number of studies have found that some endogenous pathogenic substances in patients such as beta amyloid, beta amyloid precursor, presenilin protein are closely related to abnormal potassium channel and calcium channel function, It may participate in the appearance of symptoms such as early memory loss and cognitive decline in patients by affecting the structure and regulation process of potassium channels and calcium channels.

Such as cerebral ischemia: disturbance of energy metabolism after ischemia, intracellular ATP synthesis declines, glutamic acid in synaptic space increases sharply, glutamic acid acts on NMDA receptors, causing receptor-dependent calcium channels to open, and calcium influx to increase, Calcium overload of glutamate in nerve cells can also open sodium channels through non-NMDA pathways, causing increased sodium inflow, which in turn causes chlorine and water inflow, resulting in acute osmotic swelling of nerve cells.

Drugs acting on sodium channels

Most sodium channels are voltage-gated channels, mainly to maintain the excitability and conductivity of the cell membrane.

The distribution density varies from hundreds to thousands per square micron.

Important characteristics: High selectivity to sodium, voltage dependence, fast activation and deactivation.

With activation gate, deactivation gate, voltage sensor

There are three types of drugs:

Sodium channel blockers: tetrodotoxin (TTX), dinofoxin, etc.

Drugs that promote activation: Poison toxin, Veratridine, etc.

Inactivating drugs: local anesthetics, poly-L-arginine, etc.

Drugs that block or promote inactivation of sodium channels inhibit fast sodium influx, and drugs that activate or inhibit inactivation increase sodium inward current.

Drugs acting on potassium channels

Potassium channels are widely distributed, with dozens of types;

Transient outward potassium channels: widely present in cardiomyocytes

Physiological characteristics: voltage dependence, time dependence, frequency dependence, inactivation. Appears as an instantaneous outward current (Ito) and then turns off. Ito is the main ion current involved in myocardial repolarization.

Delayed outward rectified potassium channel: Delayed outward rectified potassium channel current (Ik) can be divided into fast-activated rectified potassium current (Ikr) and slow-activated rectified potassium current (Iks)

Physiological characteristics: delayed rectification, time-dependent, voltage-dependent. Involved in the repolarization of myocardial action in place, is an important molecular target for antiarrhythmic drugs, such as class III antiarrhythmic drugs amiodarone, etc.

(3) Inward rectifying potassium channels (Kir): distributed in cardiac muscle, skeletal muscle, smooth muscle, endocrine cells, etc.

Physiological function: maintain cell resting potential, regulate vasomotor smooth muscle contraction, etc.

Tetraethylamine, Zn ²⁺ , Cd ²⁺ , Cs ⁺ , Ba ²⁺ are non-specific blocking agents; derivatives of phenylpyran are specific blocking agents.

Calcium Activated Potassium Channel (Kca)

It is widely distributed in all tissue cells except myocardium. It is a large family, divided into three sub-categories: large conductivity type (BKca), medium conductivity type (IKca) and small conductivity type (SKca). BKca plays an important role in regulating vascular smooth muscle. Its blocking agents are: iberiotoxin, chestbdotoxin.

ATP-sensitive potassium channels (KATP): distributed in pancreatic cells, neurons, smooth muscle, etc.

Blocking agents: sulfonylureas, etc.

KATP may be a drug target for anti-ischemic injury.

Drugs that act on calcium channels

Calcium channel blockers and calcium channel activators.

Calcium channel blockers

Development is extremely rapid, there are dozens of species, mainly used for cardiovascular disease treatment. Classification of International Pharmacological Society:

Class I: Drugs that selectively act on specific sites of L-type calcium channels, which are further divided according to chemical structure: Class Ia: dihydropyridines such as nifedipine; Class Ib: diltiazem such as diltiazem; Ic: benzone Amines such as verapamil; Id such as tetrandrine.

Two types: drugs that selectively act on other voltage-gated calcium channels; such as phenytoin and dextromethorphan that act on T-channel drugs; conotoxin that acts on N-channels and spider toxin that acts on P-channels

Calcium channel activator

Increase calcium influx, promote transmitter and hormone secretion, cause myocardial and smooth muscle contraction. Mainly used as a tool medicine.

Drugs acting on chlorine channels

Voltage-dependent chlorine channels, volume-activated chlorine channels, calcium-activated chlorine channels, and ligand-activated chlorine channels.