What Is Cell Signaling?

In the human body, the information transmission pathway is usually composed of specific cells that secrete and release information substances, information substances (including information substances between cells and cells, carriers, transport routes, etc.), and target cells (including specific receptors, etc.). .

Cell signaling

In the human body, the information transmission pathway is usually composed of specific cells that secrete and release information substances, information substances (including information substances between cells and cells, carriers, transport routes, etc.), and target cells (including specific receptors, etc.). .

Chinese name

Cell signaling

Foreign name

cell signaling

Cell Signaling Pathway-1. Basic Components of Information Transmission Pathway

Information transduction between human cells can be achieved through direct contact with neighboring cells, but more important and more common is the regulation of the metabolism and function of itself and other cells through the secretion of various chemical substances by cells. In humans, the information transmission pathway is usually composed of specific cells that secrete and release information substances, information substances (including information substances between cells and cells, carriers, transport routes, etc.), and target cells (including specific receptors, etc.).

Schematic of conduction pathway

Cell Signaling Pathway-2. Basic Steps of Signal Transduction

Signal transduction usually includes the following steps: specific cells release information substances information substances reach target cells through diffusion or blood circulation specifically bind to the receptors of target cells receptors convert signals and start the intracellular messenger system target cells Produce biological effects [1]. Through this series of processes, the organism responds to external stimuli.

Cell Signaling Pathway-3. Information Substances and Their Classification

Information substances can be divided into intercellular information substances and intracellular information molecules.

All chemical substances secreted by cells that regulate the life activities of target cells are collectively referred to as intercellular information substances, that is, the first messenger. According to the manner in which cells secrete information substances, they can be divided into neurotransmitters, endocrine hormones, and local chemistry. Medium and gas signal molecules. Chemical substances that transmit cellular regulatory signals in cells are called intracellular information substances, and their composition is diverse. Small molecules such as Ca2 +, cAMP, cGMP, DAG, IP3, Cer, arachidonic acid, and their metabolites that transmit information in cells are commonly referred to as second messengers. The substance responsible for the transmission of information inside and outside the nucleus is called the third messenger, which can bind to the specific sequence of the target gene and play the role of a transcription factor or a transcription regulator.

Studies have found that some information substances can bind to receptors located in the secretory cells themselves and play a regulatory role, called autocrine signals. For example, hepatocellular carcinoma cells can secrete a variety of angiogenic factors, of which VEGF is the most important stimulating factor currently found to stimulate tumor angiogenesis. Studies have shown that VEGF secreted by tumor cells in addition to the specific VEGF receptor on tumor vascular endothelial cells (Flt-1 and KDR), through tyrosine kinase-mediated signal transduction, in addition to regulating endothelial cell differentiation and angiogenesis, tumor cells themselves also express VEGF receptors, and interventions targeting VEGF and its receptors These tumor cells can change the proliferative activity and other biological characteristics in vitro. These studies indicate that the autocrine mechanism of VEGF exists in tumors [2]. The information substance produced by autocrine also has its unique and important physiological function.

Cell Signaling Pathway-4. Receptor classification and receptor-related information transduction pathways

The receptor is a component on the cell membrane or in the cell that can recognize and bind to biologically active molecules, and he can amplify and transmit the signals that are recognized and received into the cell correctly, and then cause biological effects. The receptors that exist on the cytoplasmic membrane are called membrane receptors, and the chemical essence is mostly glycosaminoglycan proteins; the receptors located in the cytosol and nucleus are called intracellular receptors, and they are all DNA-binding proteins.

4.1 Membrane receptor

(A) Circular receptors refer to ligand-dependent ion channels. When neurotransmitters bind to these receptors, they can turn ion channels on or off, thereby altering membrane permeability. Receptors play an important role in the rapid transmission of nerve impulses and participate in the rapid and precise regulation of neural reflexes.

(B) G protein-coupled receptors G protein-coupled receptors and the information transduction pathways they mediate play a vital role in the human body.

1) Structure and classification of G protein-coupled receptors

G protein-coupled receptors (GPCRs), also known as seven alpha-helix transmembrane protein receptors, are the largest protein superfamily in the body, and nearly 2,000 different GPCRs have been reported so far [3]. This type of receptor responds to a variety of hormones and neurotransmitters. Ligands mainly include biogenic amines, sensory stimuli (such as light and odor, etc.), lipid derivatives, peptides, glycoproteins, nucleotides, ions, and proteases. Wait. GPCRs are named for their ability to bind and regulate G protein activity. Most GPCRs do regulate intracellular signal transmission through G proteins, but some studies have found that some GPCRs transmit information through tyrosine kinase, Src, Stat3 and other pathways, which are related to cell proliferation and cell transformation [4].

The peptide chain of GPCRs consists of N-terminus, 7 transmembrane -helix (TM1 TM7), C-terminus, 3 extracellular loops (ECL1 ECL3) and 3 ~ 4 intracellular loops (ICL1 ICL4). The N-terminus is extracellular and the C-terminus is intracellular. Seven transmembrane -helixes repeatedly pass through the lipid bilayer of the cell membrane. Each TM consists of 20 to 27 hydrophobic amino acids, and the N-terminus has 7 to 595 amino acid residues. , C-terminus has 12 to 359 amino acid residues, and ECL and ICL each have 5 to 230 amino acid residues [3]. The high-resolution spatial structure of GPCRs has not yet been elucidated.

According to the homology of the primary structure of G protein-coupled receptors, GPCRs are mainly divided into A, B, and C3 families [5]. All three types of GPCRs have their own structural characteristics, and the specificity of the structure determines the functional uniqueness. Each type of receptor has its own unique ligand group. It is generally believed that the function of GPCRs is realized by its monomers. Recent studies have shown that GPCRs exist in dimer and multimer forms, and the study of dimers has received widespread attention. The two monomers may be covalently linked (such as a disulfide bond) or non-covalently linked (such as the hydrophobic force of a transmembrane helix), or both. Recently, people have made some progress in the study of the dimerization function of GPCRs, mainly in the following aspects: Dimerization plays a role in receptor transport; Dimerization can expand pharmacological diversity, and heterogeneity of different receptors Dimers may have more pharmacological functions than monomers; Dimerization can affect receptor activity and regulation [6].

G protein schematic

2) Structure and classification of G protein coupled to receptor

G protein is a type of peripheral protein that binds to GTP or GDP, has GTPase activity, and is located on the cytoplasmic surface of cell membranes. It consists of three subunits, namely the subunit (45kD), the subunit (35kD), and the subunit (7kD). The total molecular mass is around 100kD. G protein has two conformations. One is an trimer that is bound to GDP and is inactive. The other is that the subunit binds to GTP and causes the dimer to fall off. This is activation. type. Different types of G proteins have corresponding gene codes. Among the various G protein subunits, the subunit has the largest difference, which is often used as a marker to distinguish different G proteins.

There are many types of G proteins, including agonistic G protein (Gs), inhibitory G protein (Gi), and phospholipase C type G protein (Gp). Different G proteins can specifically couple the receptor with the corresponding effector enzyme [1]. Although G proteins are not structurally characteristic of transmembrane proteins, they can be anchored to cell membranes through lipid modification of their subunit amino acid residues. At present, G protein structure, amino acid sequence, evolutionary similarity and function have been combined as the basis for classification. It mainly includes four categories, including at least 21 different subunits, 5 different subunits, and 8 types. subunit [6].

3) Signal transduction mechanism of G protein-coupled receptors

G protein through its coupling with the receptor, often plays a role of molecular switch in the process of information transduction. Its transmembrane signal transduction is generally divided into the following steps: (1) When there is no external signal or external stimulus, the receptor does not bind to the ligand, the G protein is turned off (inactivated), and heterotrimeric It exists in the body form, that is, the subunit is tightly bound to GDP, and the subunit is loosely bound to the subunit and GDP; (2) When there is an external signal, the G protein receptor binds to its corresponding ligand and is induced accordingly The conformation of the subunit of the G protein changes, and the three subunits form a tightly bound complex, so that GDP and GTP are exchanged, but the combination with GTP causes the subunit to separate from the subunit, and the subunit is activated. That is, it is in a so-called on state, and then acts on the effector to generate intracellular signals and perform a series of transduction processes, thereby causing various reactions of the cell. (3) The subunit of G protein has GDPase activity. It can hydrolyze GTP in the presence of Mg2 +. The subunit and GDP complex recombine with the subunit to inactivate the G protein and remain in a closed state. The above three processes in turn complete the signal transmission in turn [6]. G protein mainly plays the role of molecular switch and signal amplification in the process of signal transduction. Through the cycle of G protein activation and inactivation, the information is transmitted to the cell accurately and causes a series of intracellular reactions.

4) Introduction to the major effectors of G protein and related information transduction pathways

(A) adenylyl cyclase (AC) system

The adenylate cyclase system mainly mediates the cAMP-protein kinase A pathway, which is the main pathway for hormones to regulate the metabolism of substances. Glucagon, epinephrine, and adrenocorticotrophin bind to specific receptors on the plasma membrane of target cells to form hormone receptor complexes to activate the receptors. The activated receptor catalyzes the formation of s-GTP by the G protein. The released s-GTP can activate adenylate cyclase, catalyze the conversion of ATP into cAMP, increase the cAMP concentration in the cell, cAMP can further activate PKA (protein kinase A), and PKA then passes a series of chemical reactions (such as phosphorylation Serine / threonine of other proteins) further transmit the signal for the purpose of signal transduction. Adenylate cyclase (AC) is activated by GS and inhibited by Gi. Among the isoenzymes of this cyclase, AC2 and AC4 are jointly activated by G and G subunits; AC1 type is activated by G subunits and inhibited by G, so it cannot be activated by G proteins; AC3, AC5, AC6 and AC9 Can not directly interact with G [6].

(Two) phospholipase C (PLC) system

It is an important information transduction pathway mediated by G protein-coupled receptors. After binding to specific receptors on target cell membranes, such as thyrotropin-releasing hormone, norepinephrine, and antidiuretic hormone, activated G protein directly acts on PLCB, and PLCB regulates protein transduction to activate specificity Phospholipase C (PI-PLC), which catalyzes the hydrolysis of the inner components of the membrane, phosphatidylinositol 4,5-diphosphate (PIP2), to produce inositol triphosphate (IP3) and diesteryl glycerol (DAG). Both of the latter can function as second messengers. After DAG is generated, it remains on the plasma membrane and activates protein kinase C (PKC) with the cooperation of phosphatidylserine and Ca ion. Protein kinase C can also be achieved by phosphorylating a series of target protein's silk / threonine residues. The purpose of further transducing information.

(3) Regulation of related ion channels

GS subunits have been shown to regulate at least two ion channels in recombination systems: Ca ion channels in skeletal muscle cells and Na ion channels in cardiac muscle; Gi can also inhibit Ca ion channels and activate K ion channels. G is more effective than Gi in the activation of myocardial K ion channels [6]. G protein, which regulates the opening of related ion channels to achieve information transduction, is also an effective regulation method mediated by G protein coupled receptors.

5) Prospects of G protein-coupled receptor pathways

In recent years, people have made a lot of progress in the study of G protein-coupled receptor pathways, but there are still many places that are not clear on the mechanism, mainly in the following aspects:

(1) GPCRs is obviously not just a simple switching device, but a highly dynamic structure, which is in a balance between inactive and active conformation. What are the specific mechanisms for GPCRs activation and the various regulatory mechanisms for GPCRs? The mechanism of receptor desensitization and endocytosis is still not very clear, which is an important research direction in the future [7];

(2) There are also some problems in the research of G protein. For example, G protein only provides the initial opportunity for the integration of different receptor signals and the distribution of different signals to different effector systems. Different effector systems pass Signals are transmitted in completely different ways, and physiological functions are induced, and there are few studies on the relationship between effector systems. The relationship between activated G protein and effector response is currently poorly understood. In addition, through some experiments, such as GTP binding Experiments, immune responses, isolation and purification, and molecular biology and physiological experiments have found that G protein analogs exist in plants, but it is unclear whether the structure is the same as that of animal G proteins [8];

(3) In the process of G protein transduction of information, there are many paths and related effectors. There is still a lack of a comprehensive and clear understanding of the mechanism of these effectors. Therefore, it is also extremely important to study the specific mechanism of action. Direction.

(3) Single alpha helix receptor

These types of receptors are mainly tyrosine kinase receptor type and non-tyrosine kinase receptor type. The mediated transmission pathways include the tyrosine protein kinase system, which is an important pathway for transmitting information in vivo, and so on.

(IV) Receptors with ornithine cyclase activity

4.2 Intracellular receptor

Intracellular receptors are mostly trans-acting factors. When they bind to corresponding ligands, they can bind to cis-acting elements of DNA and regulate gene transcription. Information substances that can bind to this type of receptor include steroid hormones, thyroid hormones, and retinoic acid.