G proteins. Concept and classification. G protein coupled receptors. Regulation of ion channels by G proteins. AC2 is stimulated by G-beta-gamma binding, but only in the presence of Gs-alpha

Groups C and G. Protein G is similar to protein A, but differs in specificity. Protein G has a molecular weight of 58 kDa (in the case of the C40 protein) or 65 kDa (in the case of the G148 protein). Protein G binds to the α-region of antibodies and is therefore widely used for the purification of immunoglobulins. G protein molecules also bind albumin.

Other immunoglobulin binding proteins

There are other bacterial proteins that bind immunoglobulins - protein A, protein A/G and protein L. These proteins are used for purification, immobilization and isolation of immunoglobulins. These antibody binding proteins have different immunoglobulin binding profiles.

see also

Links

• http://www.jbc.org/cgi/reprint/266/1/399 Sjobring U, Bjorck L, Kastern W, Streptococcal protein G. Gene structure and protein binding properties, J Biol Chem. 1991 Jan 5;266(1):399-405

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See what “Protein G” is in other dictionaries:

- (English protein A) is a protein with a molecular weight of 40-60 kDa, isolated from the surface of the cell wall of Staphylococcus aureus (Staphylococcus aureus). Protein A is used in biochemical research, as it binds well many... ... Wikipedia Gawk at Arab squirrels.. Dictionary of Russian synonyms and similar expressions. under. ed. N. Abramova, M.: Russian Dictionaries, 1999. protein globulin, histone, proteinoid, protein, protein body, protamine, proteid Dictionary of Russian synonyms ...

Synonym dictionary

Ushakov's Explanatory Dictionary Synonym dictionary

Ushakov's Explanatory Dictionary Synonym dictionary

1. PROTEIN1, squirrel, male. (biol. chem.). The most important component of the body of animals and plants; the same as albumin and protein. 2. PROTEIN2, squirrel, male. 1. Convex opaque shell of the eye. || only plural Eyes (simple). Bulge out the whites. Proteins... ... protein C - Protein, serine protease, synthesized by liver cells; anticoagulant, is an inhibitor of blood clotting factors Va and VIIIa; the frequency of heterozygotes for B.C deficiency in human populations reaches 1/200; this anomaly is associated with increased... ...

PROTEIN, an organic COMPOUND containing many AMINO ACIDS connected by covalent peptide bonds. Protein molecules consist of polypeptide chains. There are about 20 different amino acids in living CELLS. Due to the fact that in each... ... Scientific and technical encyclopedic dictionary

PROTEIN, lka, husband. A high-molecular organic substance that ensures the vital functions of animal and plant organisms. | adj. protein, oh, oh. Protein feed (high protein content). II. PROTEIN, lka, husband. 1. The transparent part of the egg... Ozhegov's Explanatory Dictionary

Fatty acid binding protein (FABP) is a family of transporters of fatty acids and other lipophilic substances such as eicosanoids and retinoids. It is believed that these... ... Wikipedia

1. PROTEIN, lka; m. 1. The transparent liquid surrounding the yolk of a bird's egg. / About this part of a chicken egg as food. Drink raw b. Whipped whites. ◁ Protein, oh, oh. B. cream (from egg whites). 2. PROTEIN see 1. Proteins. 3. PROTEIN see 2. Proteins. 4.… … encyclopedic Dictionary

(English) Guanine nucleotide-binding proteins, Guanyl nucleotide binding proteins are a family of proteins involved in eukaryotic cell signaling. G proteins play the role of a kind of switches: they can switch from an inactive state to an active one and vice versa, accordingly turning on or off the transmission of a certain signal inside the cell. These proteins received their name for their ability to bind guanyl nucleotides. G uanine nucleotide): in a complex with guanosine diphosphate (GDP) they are inactive, and in a complex with guanosine triphosphate (GTP) they are active.

The term "G proteins" is more often used to refer to heterotrimeric (large) GTP-binding proteins consisting of three subunits α, β and γ; There is another class of GTP-binding proteins - monomers, which are sometimes called small G-proteins (superhome of Ras small GTPases), they are homologous to the α-subunits of large ones.

Heterotrimeric G proteins are involved in the transmission of signals from G protein-coupled receptors. G-protein coupled receptors (GPCR)- the largest class of cellular receptors (for example, in Caenorhabditis elegans their genes occupy 5% of the entire genome). In vertebrates, they are responsible for the cell's perception of a number of hormones and other signaling molecules, as well as for the chemical senses (smell and taste) and photoreception (vision). It is significant that approximately half of the known pharmaceutical drugs act through G-protein coupled receptors: these include well-known medications, such as the antihistamines Claritin (loratadine) and the antidepressant Prozac (Fluoxetine), as well as psychotropic substances, in particular heroin, cocaine and tetrahydrocannabinol (active ingredient in marijuana).

Heterotrimeric G proteins were discovered by Alfred Gilman and Martin Rodbell, for which they received the Nobel Prize in Physiology or Medicine in 1994.

Structure of heterotrimeric G proteins

Hetrotrimeric G proteins consist of three subunits: α, β and γ. The α subunit contains a GTP binding and hydrolysis domain that is identical throughout the GTPase superhomeland. The β-subunit contains 7 β-structures organized like propeller blades. The γ-subunit closely interacts with the β-subunit; together they form a single functional structure, which can dissociate only in the case of protein hydrolysis. The entire G protein is anchored in the membrane by two lipids, one of which is covalently attached to the N-terminus of the α-subunit, the other to the C-terminus of the γ-subunit.

G protein-coupled receptors

G protein coupled receptors G-protein coupled receptors, GPCR)- the largest family of cellular receptors in eukaryotes, providing the perception of hormones, neurotransmitters, local regulators, and also provide vision, smell and sense of taste in vertebrates. About 700 GPCR genes are found in the human genome, and in the mouse there are more than 1000 of these receptors for the sense of smell alone.

Signal molecules that act as ligands for G protein-coupled receptors can be very different in chemical nature: proteins, small peptides, lipids, amino acid derivatives, and the like. In addition, some members of this class of receptors, in particular rhodopsin, can perceive photons of light. Sometimes several different GPCRs exist for a single signaling molecule, are expressed in different cell types, and trigger different signaling pathways. For example, in the human body there are at least 9 different receptors for adrenaline and at least 14 for the neurotransmitter serotonin.

All G protein-coupled receptors have a similar structure: they consist of a single polypeptide chain that crosses the lipid bilayer 7 times. Each transmembrane domain is represented by an α-helix, which includes 20-30 nonpolar amino acids. These domains are interconnected by loops of various sizes located on both sides of the plasma membrane. GPCRs are predominantly glycoproteins, the carbohydrate residues of which are located on the glycoprotein side. The intracellular domains of these receptors contain interaction sites with G proteins.

Functional cycle of G proteins

G proteins serve the role of coupling cellular receptors with certain effector molecules, such as enzymes or ion channels, while they act as molecular switches. In the inactive state, G proteins contain GDP bound to the α subunit.

Signal transmission begins when the appropriate ligand acts on the cellular receptor, as a result of which the receptor is activated and changes conformation. The activated receptor influences the G protein (which is either permanently complexed with it or associates after activation), causing the structure of the α subunit to change in such a way that it releases the bound GDP molecule. The place of this molecule is quickly taken by GTP, which leads to activation of the G-protein and changes in its structure: the α-subunit loses affinity for the βγ-complex, and it disintegrates. In such an activated state, both the GTP-bound α-subunit and the βγ-complex can carry out signal transmission: activate certain enzymes or influence the state of ion channels. The α-subunit is a GTPase, and as soon as it hydrolyzes the attached GTP to GDP, it is immediately inactivated, and the trimmer structure of the G-protein is restored. This way the sound is turned off. The inactivated G protein can interact with a subsequent receptor molecule and turn back on.

Regulation of G-protein activity

The efficiency of transmission of a particular signal through the G protein depends on the ratio between the concentration of the active, GTP-bound, and inactive, GDP-bound forms. And this ratio, in turn, depends on two states: the dissociation constant of GDP, and the rate constant of GTP hydrolysis:

Where

• G-protein · GTP—concentration of the active form of G-protein;
• G-protein · GDP - concentration of the inactive form of G-protein;
• k diss, GDP—GDF dissociation constant;
• k cat, GTP is the rate constant of GTP hydrolysis.

This relationship is confirmed by an excess of GTP in the medium, as well as its rapid, almost instantaneous, binding to an “empty” G-protein molecule (that is, not associated with one guanyl nucleotide). In this case, the efficiency of signal transmission can be adjusted in one of the following ways:

• An increase in k diss, GDP, which is ensured by special proteins - guanyl nucleotide exchange factors (eng. Guanine nucleotide exchange factors, GEFs), promotes intensification of signal transmission. For heterotrimeric G proteins, these factors are activated receptors (GPCRs) bound to the appropriate ligand.
• A decrease in k diss, GDP, which is ensured by inhibitors of guanyl nucleotide dissociation. Guanine nucleotide dissociation inhibitors (GDI). Proteins with such functions have so far been found for the Ras superhomeland of small GTPases; their function is to maintain a constant pool of inactivated GDP-bound molecules in the cytoplasm;
• The increase in k cat, GTP, that is, the rate of GTP hydrolysis, is carried out thanks to GTPase-activating proteins. GTPase activating proteins, GAPs). This reduces the lifespan of activated G protein molecules. The activity of GAPs is usually regulated by other signaling pathways. Proteins that accelerate the hydrolysis of GTP by the α-subunit of heterotrimeric G-proteins are called G-protein signaling regulators. Regulator of G protein signaling, RGS), There are about 25 RGS genes in the human genome, each of which interacts with a characteristic set of G proteins.

Signaling pathways activated by G proteins

G proteins receive input from their associated receptors, after which they activate one of the cell's signaling pathways.

Effect on the synthesis of cyclic AMP

Cyclic AMP (cAMP) is a common second messenger that controls many processes in eukaryotic cells. cAMP is synthesized with ATP by the large transmembrane enzyme adenylate cyclase and degraded by cAMP phosphodiesterase. Many signaling molecules influence the cell by increasing or decreasing the concentration of cAMP through activation or inhibition of adenylate cyclase. cAMP performs its function as a second messenger by activating cAMP-dependent protein kinase (protein kinase A, PKA), which in turn phosphorylates many proteins in the cell at serine and threonine residues, activating or deactivating them.

There are two types of G proteins that influence active adenylate cyclases: G s (eng. Stimulating)- stimulating, activating it and increases the concentration of cAMP and G i (eng. Inhibitory)- inhibitory, suppressing adenylate cyclase, but also acts by direct action on ion channels. Examples of reactions triggered by a G s dependent increase in cAMP concentration are:

• Synthesis and secretion of thyroid hormones by the thyroid gland under the influence of thyroid-stimulating hormone;
• Secretion of cortisol by the adrenal cortex under the influence of adrenocroticotropic hormone;
• The breakdown of glycogen in muscles under the influence of adrenaline;
• The breakdown of glycogen in the liver under the influence of glucagon;
• An increase in the frequency and strength of heart contractions under the influence of adrenaline;
• Reabsorption of water in the kidneys under the influence of parathyroid hormone;
• The breakdown of triglycerides in adipose tissue under the influence of one of the daily hormones: adrenaline, ACTH, glucagon, thyroid-stimulating hormone.

Bacterial toxins affecting the activity of G s and G i proteins

G-proteins, which influence cAMP-dependent cellular signaling, are targets of bacterial toxins:

• Cholera toxin is an enzyme that catalyzes the transfer of ADP-ribose from NAD+ (ADP-ribosylation) to the α-subunits of the G s protein. As a result, it loses the ability to hydrolyze the bound GTP molecule and enters a state of permanent activation. This in turn leads to a long-term increase in the concentration of cAMP in the cells of the wall of the large intestine, due to which a large amount of water and Cl - ions begin to be released into its lumen. This is how diarrhea occurs and is a characteristic sign of cholera.
• Pertussis toxin carries out APD-ribosylation of the α-subunit of the G i protein, due to which it cannot interact with the corresponding receptor and turn on.

These two toxins are used in biological studies to determine which cellular response is mediated by the G s - or G i -protein.

Activation of phospholipase C-β

Many G protein-coupled receptors act by activating phospholipase C-β (PLC-β). This enzyme acts on the inositol phospholipid: phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2 or PIF 2), present in small quantities in the inner leaflet of the lipid bilayer of the plasma membrane. The receptors that activate this signaling pathway are usually coupled to the G q -block, which activates phospholipase C in a similar way to the G s -block - adenylate cyclase. Activated phospholipase breaks down phosphatidylinositol 4,5 bisphosphate to inositol 1,4,5 triphosphate (IP 3) and diacyglycerol (DAG). At this stage, the signaling pathway branches:

• IP 3 from the plasma membrane diffuses into the cytosol, where it subsequently attaches to calcium channels on the surface of the endoplasmic reticulum and opens them. This leads to a sharp increase in the concentration of Ca + ions in the cytoplasm. This molecule is also an important second messenger and regulates many cellular processes.
• DAG remains embedded in the membrane, where it can be a substrate for the synthesis of eicosanoids, including prostaglandins, involved in pain and inflammation. DAG also activates serine/threonine protein kinase C, the activity of which also depends on calcium.

Examples of cellular reactions of G protein-dependent activation of phospholipase C-β are:

• The breakdown of glycogen in the liver under the influence of vasopressin;
• Secretion of amylase by the pancreas under the influence of acetylcholine;
• Contraction of smooth muscles under the influence of acetylcholine;
• Platelet aggregation under the influence of thrombin.

Regulation of ion channels by G proteins

Many G proteins act by opening or closing ion channels, thereby changing the electrical properties of the plasma membrane.

For example, a decrease in the frequency and strength of heart contractions under the influence of acetylcholine occurs due to the fact that muscarinic acetylcholine receptors, after activation, interact with the G i -bill, the α-subunit of which suppresses the activity of adenylate cyclase, while the βγ-complex opens potassium channels in the plasma membrane of cardiac cells muscles, due to which their excitability decreases.

Other G proteins regulate the activity of ion channels indirectly: for example, vision and olfactory receptors act through G proteins, which affect the synthesis of cyclic nucleotides, in turn closing or opening ion channels (ion channels controlled by cyclic nucleotides). For example, all olfactory receptors are associated with the G olf protein, which activates adenylate cyclase; The cAMP that is synthesized opens sodium channels, which leads to depolarization of the membrane and the generation of a nerve impulse (receptor potential) that is transmitted to neurons.

In the rods of the human retina, the light-sensitive molecule is rhodopsin. The plasma membrane of these cells contains a large number of cGMP-gated cation channels. In the absence of light stimulation, the cytoplasm of the rods contains a high amount of cGMP, which keeps the cation channels open. As a result, the membrane periodically depolarizes and synaptic transmission of impulses to neurons occurs. After activation by light, rhodopsin changes conformation and interacts with the G protein transducin (Gt). After this, its α-subunit activates cGMP phosphodiesterase, which breaks down cGMP, as a result of which the cation channels close and synaptic transmission stops. It is the decrease in the frequency of impulses coming from light-sensitive cells that is perceived by the brain as a sensation of light.

G protein families

All heterotrimeric G proteins are divided into four main families based on the amino acid sequence of the α subunit:

(C protein coupled receptors, GPCRs), transmit a signal from primary messengers to intracellular targets using the GPCR-^-G-protein^-effector protein cascade. The primary signals for these receptors are a wide variety of molecules, for example, low molecular weight hormones and neurotransmitters (such as adrenaline, norepinephrine, acetylcholine, serotonin, histamine), opioids, peptide and protein hormones (adrenocorticotropin, somaostatin, vasopressin, angiotensin, gonadotropin , epidermal growth factor), some neuropeptides.

The same series includes many chemical signals perceived by olfactory and gustatory sensory cells, and light, the receptor for which is the pigment of visual or photoreceptor cells rhodopsin.

It should be taken into account that the same primary signal can initiate signal transmission through several (sometimes more than 10) different GPCRs, so if the number of external signals for GPCRs is several dozen, then more than 200 such receptors themselves are known.

With all their diversity, GPCRs are monomeric integral membrane proteins, the polypeptide chain of which crosses the cell membrane seven times. In all cases, the receptor site responsible for interaction with the primary signal is localized on the outer side of the membrane, and the region in contact with the G protein is on its cytoplasmic side.

The downstream component of the GPCR signal transduction cascade is represented by the G protein. About 20 different G proteins have been found, among them, first of all, G s and C; should be mentioned, which respectively stimulate and inhibit adenylate cyclase; G q , activating phospholipase C; G-proteins of sensory cells: photoreceptor - G t (transducin), olfactory - G o if and gustatory - G g.

C-proteins are heterotrimers that consist of three types of subunits: ct, (S and y), but under natural conditions the last two subunits function as a single Ru-complex. The most important characteristic of C-proteins is the presence of a guani binding center on their a-subunit - nucleotides: GDP and GTP (Figures 139, 145). If GTP is bound to the C-protein, then this corresponds to its activated state. If GDP is present in the nucleotide-binding center, then this form corresponds to the inactive state of the protein (Figure 79).

The central event in the transmission of a signal from the receptor, which is affected by the primary signal, to the G protein is that the activated receptor catalyzes the exchange of GDP bound to the G protein for GTP present in the environment. This GDP/GTP exchange on the G protein is accompanied by the dissociation of the trimeric G protein molecule into two functional subunits: the α subunit containing GTP and the Py complex (Figures 139, 145).

Next, one of these functional subunits, which one depends on the type of signaling system, interacts with the effector protein represented by an enzyme or ion channel. As a consequence, their catalytic activity or ionic conductance changes accordingly, which, in turn, leads to a change in the cytoplasmic concentration of the secondary messenger (or ion) and, ultimately, initiates one or another cellular response.

Effector proteins in signaling systems such as GPCR-G-protein-effector protein can be adenylate cyclase, which catalyzes the synthesis of cAMP from ATP; phospholipase C, which hydrolyzes phosphatidylinositol to form DAT and 1P3; phosphodiesterase, which breaks down cGMP to GMP; some types of potassium and calcium channels.

It is important that during signal transmission in the G-protein–effector protein receptor cascade, the original external signal can be amplified (amplified) many times over. This occurs due to the fact that one receptor molecule, while in the activated state (R*), manages to convert several G-protein molecules into the activated form (G*).

For example, in the visual cascade, rhodopsin^C^ecGMP-phosphodiesterase for each R* molecule can produce several hundred or even thousands of Gt* molecules, which means that at the first stage of the 7?*-»G* cascade the amplification factor of the external signal is 10 2 -10 3 . Although at the next stage of the cascade (C*^effector protein) each G* molecule interacts with only one molecule of the effector protein, the signal here is also amplified, since for each molecule of G* and, accordingly, of the activated effector protein, many appear (or disappear) in the cytoplasm secondary messenger molecules. Thus, in the visual cascade at its second stage, one molecule of activated cGMP phosphodiesterase is capable of breaking down up to 3000 molecules of cGMP per second, which serves as a secondary messenger in photoreceptor cells.

The total gain of the cascade is equal to the product of the gains at all stages of the cascade. The amplification coefficient of the signal as it passes through the cascade can reach very high values: in visual cells this is a value of the order of 10 5 -10 6 .

The cessation of the external stimulus is accompanied by the switching off of all components of the signaling system. At the receptor level, this is achieved, firstly, as a result of dissociation of the primary messenger from the complex with GPCR, and secondly, by phosphorylation of receptors under the action of special protein kinases and subsequent binding to a modified receptor of a special protein (for example, P-arrestin) .

G-proteins have GTPase activity, that is, the ability to hydrolyze the GTP associated with them to GDP, which ensures their self-exclusion, that is, the G-GTP-e G-GDP transition. Since the state of activation of the effector protein (on-off) directly depends on the state of the G-protein, this transition also means the switching off of the effector protein, and, consequently, the cessation of synthesis (hydrolysis) of the secondary messenger or the closure of the ion channel.

And finally, in order for the cell’s transition to its original (before the external stimulus) state to be completed, special mechanisms restore the initial level of the secondary messenger or cation in its cytoplasm. For example, cAMP, the cytoplasmic concentration of which increases during signal transmission in the P-adrenergic receptor cascade C 5 -protein-adenylate cyclase, is then hydrolyzed by cAMP phosphodiesterase to non-cyclic (linear) AMP, which does not possess the properties of a secondary messenger.

TRANSMEMBRANE SIGNAL TRANSMISSION. An important property of membranes is the ability to perceive and transmit signals from the external environment into the cell. “Recognition” of signaling molecules is carried out with the help of receptor proteins built into the cell membrane of target cells or located in the cell.

If the signal is perceived by membrane receptors, then the information transmission scheme can be represented as follows:

interaction of the receptor with a signaling molecule (primary messenger);

activation of the membrane enzyme responsible for the formation of the second messenger;

formation of the secondary messenger cAMP, cGMP, IP3, DAT or Ca 2+;

activation by mediators of specific proteins, mainly protein kinases, which, in turn, by phosphorylating enzymes, influence the activity of intracellular processes.

There are several mechanisms for transmembrane information transfer: using the adenylate cyclase system, inositol phosphate system, catalytic receptors, cytoplasmic or nuclear receptors.

Structural and functional organization of G-proteins

G-proteins (GTP-binding proteins) are universal intermediaries in transmitting signals from receptors to cell membrane enzymes that catalyze the formation of second messengers of the hormonal signal. G proteins are oligomers consisting of α, β and γ subunits.

Each α-subunit in the G protein has specific centers:

binding of GTP or GDP;

interactions with the receptor;

binding to βγ subunits;

phosphorylation by protein kinase C;

interaction with the enzyme adenylate cyclase or phospholipase C.

The structure of G proteins lacks α-helical, membrane-spanning domains. G proteins belong to the group of “anchored” proteins.

Regulation of G-protein activity

There is an inactive form of the G protein - the αβγ-GDP complex and the activated form αβγ-GTP. Activation of the G protein occurs upon interaction with the activator-receptor complex; a change in the conformation of the G protein reduces the affinity of the α-subunit for the GDP molecule and increases it for GTP. Replacement of GDP with GTP in the active site of the G protein disrupts the complementarity between α-GTP and βγ subunits. The receptor associated with the signaling molecule can activate a large number of G protein molecules, thereby providing amplification of the extracellular signal at this stage.

Activated G protein α-subunit (α-GTP) interacts with a specific cell membrane protein and modifies its activity. Such proteins can be the enzymes adenylate cyclase, phospholipase C, cGMP phosphodiesterase, Na+ channels, K+ channels.

Rice. 5-35. Cycle of G-protein functioning. R s - receptor; G - hormone; AC - adenylate cyclase.

The next stage of the G-protein functioning cycle is dephosphorylation of GTP bound to the α-subunit, and the enzyme that catalyzes this reaction is the α-subunit itself.

Dephosphorylation results in the formation of an α-GDP complex, which is not complementary to a specific membrane protein (for example, adenylate cyclase), but has a high affinity for py protomers. The G protein returns to its inactive form, αβγ-GDP. With subsequent activation of the receptor and replacement of the GDP molecule with GTP, the cycle repeats again. Thus, the α-subunits of G proteins shuttle to carry a stimulatory or inhibitory signal from a receptor that is activated by a primary messenger (eg, a hormone) to an enzyme that catalyzes the formation of a secondary messenger.

Some forms of protein kinases can phosphorylate the α-subunits of G proteins. The phosphorylated α-subunit is not complementary to a specific membrane protein, such as adenylate cyclase or phospholipase C, and therefore cannot participate in signal transduction.

Adenylate cyclase

The enzyme adenylate cyclase, which catalyzes the conversion of ATP to cAMP, is a key enzyme in the adenylate cyclase signal transduction system. The enzyme belongs to the group of integral proteins of the cell membrane; it has 12 transmembrane domains. Extracellular fragments of adenylate cyclase are glycosylated. The cytoplasmic domains of adenylate cyclase have two catalytic centers responsible for the formation of cAMP, a second messenger involved in the regulation of the activity of the protein kinase A enzyme.

The activity of adenylate cyclase is influenced by both extracellular and intracellular regulators. Extracellular regulators (hormones, eicosanoids, biogenic amines) carry out regulation through specific receptors, which, using the α-subunits of G proteins, transmit signals to adenylate cyclase. The α s-subunit (stimulating), when interacting with adenylate cyclase, activates the enzyme, the α-subunit (inhibitory) inhibits the enzyme. Of the 8 studied isoforms of adenylate cyclase, 4 are Ca 2+ -dependent (activated by Ca 2+). Regulation of adenylate cyclase by intracellular calcium allows the cell to integrate the activities of the two major second messengers cAMP and Ca 2+ .

Adenylate cyclase system

With the participation of the adenylate cyclase system, the effects of hundreds of signaling molecules of different nature - hormones, neurotransmitters, eicosanoids - are realized.

The functioning of the transmembrane signaling system is ensured by proteins: Rs-receptor of the signal molecule, which activates adenylate cyclase, and R i -receptor of the signal molecule, which inhibits adenylate cyclase; G s -stimulating and G j -adenylate cyclase-inhibiting proteins; enzymes adenylate cyclase (AC) and protein kinase A (PKA).

The sequence of events leading to the activation of adenylate cyclase:

binding of an activator of the adenylate cyclase system, for example, hormone (G) to the receptor (R s), leads to a change in the conformation of the receptor and an increase in its affinity for the G s protein.

As a result, the complex [G][R][O-GDP] is formed;

the addition of [G][R] to G-GDP reduces the affinity of the α-subunit of the G s protein for GDP and increases the affinity for GTP. GDP is replaced by GTP;

this causes dissociation of the complex.

The separated α subunit, associated with a GTP molecule, has an affinity for adenylate cyclase:

[G][R] → [G][R] + α-GTP + βγ;

Conformational changes in the [α-GTP][AC] complex stimulate an increase in the GTP-phosphatase activity of the α-subunit. The GTP dephosphorylation reaction occurs, and one of the reaction products, inorganic phosphate (Pi), is separated from the α-subunit, and the [α-GDP] complex is retained; the rate of hydrolysis determines the signal transmission time;

the formation of a GDP molecule in the active center of the α-subunit reduces its affinity for adenylate cyclase, but increases its affinity for βγ-subunits.

The G s protein returns to its inactive form;

Adenylate cyclase system

if the receptor is associated with an activator, for example a hormone, the cycle of G s protein functioning is repeated.

The most important intracellular component of signaling cascades are G proteins. Currently, about 20 different G proteins are known. For example, Gs and Gi stimulate and inhibit adenylate cyclase, respectively; Gq activates phospholipase C. Among the G proteins of sensory cells we can note: photoreceptor - Gt (transducin), olfactory - Golf and gustatory - Gg.

In terms of their structure, G proteins are heterotrimers consisting of three types of subunits: a (alpha), b (beta) and g (gamma), however, under native conditions, beta and gamma subunits function as a single complex. A common structural feature of G proteins is the presence of seven transmembrane alpha helices. The most important characteristic of G proteins is the presence on their α-subunit of a binding center for guanyl nucleotides: GDP (guanisidine diphosphate) and GTP (guanisidine triphosphate). If GTP is bound to a G protein, then this corresponds to its activated state (G-GTP) or, otherwise, the G protein is in an activated position. If GDP is present at the nucleotide-binding site, then this form (G-GDP) corresponds to the “off” state. The key point in signal transmission from the receptor (which was affected by the primary signal) to the G protein is the catalysis by the activated receptor of the exchange of GDP bound to the G protein to the GTP present in the environment (GDP / GTP exchange on the G protein). Transmembrane receptors provide the basic vital functions of the cell: signaling, transport, protection. The study of the mechanism of action of various biologically active compounds, including antiviral and antibacterial ones, has shown that the most specific targets for both medicinal and toxic compounds (poisons) are the cellular receptors of humans and pathogenic microorganisms. A significant portion of transmembrane receptors are About half of all currently known drugs act specifically on GPCRs. Of all types of cell surface receptors, GPCRs are the most universal. These receptors bind a wide range of molecules, from small neurotransmitters to large proteins. GPCRs are involved in almost all vital processes.

The diversity of signals transmitted by GPCRs is ensured by the functional coupling of different GPCRs with each other. Thus, it is obvious that the most universal mechanism of the influence of toxic and medicinal compounds on the cell is realized through the effect on the cell’s receptor apparatus, by changing their conformation or the main characteristics of the ligand-receptor connection, their specificity and reversibility.