A brief talk on the GPCR antibody

  • The human body is made up of tens of trillions of cells, different cells not only carry out their own life activities, but also through some way to establish contact with the surrounding cells, or other cells farther away, so that this huge multi-cellular machine can run steadily under the close monitoring of the body. Cells transmit information through certain chemical signals. When these chemical signals reach specific cells, they lead to specific metabolic processes or changes in gene expression in cells, which ultimately manifest specific physiological responses. This process is called cellular signal transduction.

    Many chemicals can transmit information between cells, such as proteins, polypeptides, amino acids, nucleotides, steroids and so on. The gas molecule NO is also an important signal molecule. We call these molecules that transfer information between cells called transport proteins. The transport protein must combine specific receptors to complete the mission of transmitting signals to target cells. Receptors are proteins located in specific parts of target cells that bind to library sequencing and initiate specific signal processes in target cells. According to the different localization in target cells, receptors can be divided into cell surface receptors and intracellular receptors. The former includes ion channel-coupled receptors, G protein-coupled receptors and enzyme-linked receptors, while the latter can be located in both cytoplasm and nucleus.

    When the transport protein outside the membrane acts on the receptor, the inner part of the membrane of the receptor binds to the G protein and activates the G protein. G protein can transmit extracellular information in two ways: the first way is to open the transmembrane ion channel, allowing bioactive peptide to enter; the second way is to activate the second messenger, such as cAMp, IP3 / DAG. Calcium is usually considered the third messenger downstream of cAMp and IP3/DAG.

    G protein coupled receptor (GPCR) is one of the target enzymes. The key to the research and development of modern new drugs is to find, determine and prepare drug screening targets - molecular drug targets. Drug targets refer to the binding sites of drugs in vivo, including gene sites, membrane protein, receptors, enzymes, ion channels, nucleic acids and other biological macromolecules. The determination of new effective drug targets is the primary task of new drug development. To date, about 500 therapeutic targets have been identified, of which G-protein coupled receptor (GPCR) targets account for the majority.

    The combination of transport protein selectively with receptors is a universal mechanism of cell signal transduction. This process is crucial because it allows the cell to select the signal it needs from a complex and changeable extracellular flow of information and pass it on to initiate the response. The same transport proteins may have different effects on different cells, such as acetylcholine, which increases the contractility of skeletal muscle cells but decreases the contractility of cardiac muscle cells, because skeletal muscle and cardiac muscle cells perceive acetylcholine receptors differently. But sometimes the same transport protein binds to the same receptor, and still exhibits different physiological effects in different cells, because in different cells, the same transport protein binds to the receptor, but activates completely different downstream signaling pathways. This mechanism enables relatively limited types of transport proteins and receptors to initiate multiple signaling pathways in different cells, thereby fine-tuning the various life activities of cells.

    G protein coupled receptors (GPCRs) are ubiquitous in organisms and are the largest number of cell surface receptor families in the body membrane transportation. It is because of these "smart" receptors on the cell membrane, the existence of GPCR, the human body can feel the colorful world. At present, there are more than 800 G protein-coupled receptor members, which have similar structure: the whole peptide chain must cross the membrane seven times repeatedly, the amino terminal is located outside the membrane, the carboxyl terminal is located inside the membrane, and the ring structure formed by the transmembrane is the site where it binds to the transport protein. This structure of GPCR is evolutionarily conserved, and similar structures can be found even in two distantly related species, such as bacteriorhodopsin in bacteria. G protein-coupled receptors are named because GPCR is located upstream of the trimer G protein in cell signaling pathways, and when it binds to transport proteins, its further signal transduction depends on G protein.

    GPCR-mediated signal transduction system consists of G protein-coupled receptor (GPCR), G protein and effector. The binding sites of different transport proteins on G protein coupled receptors are also different. When the specific transport protein binds to the GPCR on the membrane, the structure of GPCR changes, and the corresponding G protein is activated, which catalyzes the replacement of guanosine diphosphate (GDP) with guanosine triphosphate (GTP), thereby altering the conformation of Galpha subunit, reducing the affinity of G protein alpha subunit and anti idiotype, and dissociating the trimer into Galpha-gamma subunit. GTP and G beta gamma two polymers. Dissociated Galpha-GTP and Gbeta-gamma regulate downstream effectors to produce second messengers, which affect intracellular metabolic pathways through cascade amplification or alter the expression of related genes in the nucleus to induce physiological and biochemical reactions.

    G protein-coupled receptors play an important role in regulating the physiological processes mediated by peptide hormones, neurotransmitters, growth factors, light and odor. For example, when you encounter an emergency, the secretion of adrenaline (a transport protein) suddenly increases and binds to the corresponding adrenergic receptor (a GPCR), inducing the part of the GPCR located in the cell membrane to bind to the G protein in the cell and activate the G protein through the G protein to exert various effects. The transmission of vision, taste and smell signals is also inseparable from GPCR. For example, visual signals are essentially light-induced conformational changes in rhodopsin (a GPCR), and through a series of signal transduction, eventually leading to the closure of the corresponding ion channels on the optic cells, the hyperpolarization of the plasma membrane antibody on both sides of the optic cells, this signal into the brain, and eventually produce vision. There is a taste transduction protein in the process of transmitting taste signals, which is concentrated in the taste buds on the surface of the tongue. When you taste sweets, sweet molecules bind to the corresponding receptor (GPCR) in the sweet bud and activate the free antibodies, which shuts down the K + channel on the membrane, leading to cell depolarization and eventually sweet taste. Other taste signal transductions are similar, except that the second messenger used is different from the ion channel controlled. The same mechanism was used for olfactory signal transduction, and Axel and Barker won the Nobel Prize in physiology or medicine in 2004 for their discovery.

    In addition, many human diseases are closely related to G protein coupled receptors. GPCR can be used as a good drug target because of its structural characteristics and its important role in cell signal transduction and antibody repertoire. Therefore, more and more modern drugs are targeting at G protein-coupled receptors. Therefore, the study of the mechanism of these processes also points out the direction for better drug development.

    In summary, GPCR-mediated cell signal transduction pathways have extremely diverse types and very precise regulatory mechanisms, and participate in many aspects of biological regulation. Further study of this signaling pathway will help us better understand our own life activities.