BIOCHEMISTRY - Textbook - Ostapченко L. I. - 2012

Chapter 4. MOLECULAR ORGANIZATION AND BIOLOGICAL FUNCTIONS OF MEMBRANES

4.3. Membrane functions

4.3.3. Membrane receptors and transduction of external signals

An important function of membranes is the Selection and Amplification of signals from the external environment that regulate cellular METABOLISM. In most cases, primary signals (messengers) that inform The Cell of the need to alter metabolic intensity deliver this information to The Plasma Membrane but do not penetrate it. Examples of primary messengers include Hormones, Neurotransmitters, and many xenobiotics. Due to their specific molecular Structure, messengers bind to Membrane Receptors and activate them. Activation of receptor systems involves the following stages:

✵ binding of a Ligand (or agonist) to the receptor;

✵ transmission of information about ligand-receptor binding into the plasma membrane and into the cell;

✵ cellular response, which, in turn, is divided into rapid, slow, and late (Fig. 4.16).

Several families of receptor Proteins with homologous primary structures are known. These families consist of structurally related (but functionally distinct) proteins (Table 4.3).

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Fig. 4.16. Diagram of cellular signal Transduction systems:

R - receptor, G - G-protein, E - enzyme that generates a second messenger, ER - Endoplasmic reticulum,

PK - protein kinase, LR - ligand-receptor complex. Early genes - response within 15-20 min, late genes - within hours and days. 1-3 - signal transduction systems

Table 4.3

Major families of membrane receptors in eukaryotes

The signal generated at (or within) the plasma membrane in response to receptor activation leads to The formation of a second messenger on the other side of the membrane—in the Cytosol and the inner monolayer of the membrane. This multi-step process, which occurs with amplification at each stage, ensures that the information of the primary messenger is not lost. The efficiency of this process depends not only on the magnitude of the external signal but also on the viscosity of the lipid environment in which it takes place. More than ten second messengers are already known to exist in various Tissues and in different ratios.

Thus, there are Two main mechanisms of external signal transduction into the cell (Fig. 4.16, 3). A "hydrophobic" signal (Steroid Hormones, iodothyronine, Vitamins A and D) penetrates the plasma membrane, then passes through the cytosol into The Nucleus and Mitochondria, where it forms a complex with nuclear (or mitochondrial) receptors and alters template synthesis (or ATP synthesis). In the second pathway, the ligand-receptor complex is formed on the outer side of the plasma membrane, which triggers either the rapid opening of an ion channel and the influx of Na⁺ ions into the cell (Fig. 4.16, 1), generating an Action Potential, or the activation of systems triggered by second messengers, leading to slower changes in cellular metabolism (Fig. 4.16, 2). The set of mechanisms for transducing intercellular signals into intracellular (including intraorganellar) ones are called signal transduction systems. The four main and most studied systems of hormonal signal transmission across the plasma membrane are shown in Fig. 4.17.

Many hormones (amines, Peptides, proteins, Prostaglandins), as well as odor and taste, act through the formation of cyclic adenosine monophosphate (cAMP) (Table 4.4). The Formation of the hormone-receptor complex via G-proteins (GTP-binding proteins) activates or blocks adenylate cyclase, which produces cAMP from ATP. This intracellular messenger triggers the dissociation of cAMP-dependent protein kinase A (PKA) into regulatory and catalytic subunits (cAMP + PkR → cAMP-R + Pk). The latter is activated and phosphorylates many proteins, thereby converting them into an active state. This increases, for example, lipid breakdown and Glycogenolysis, catecholamine synthesis, cardiac contraction, and other processes associated with an overall increase in functional activity.

Fig. 4.17. Major cellular signal transduction systems:

AC - adenylate cyclase, GC - guanylate cyclase, CaM - calmodulin, CaM-PK - calmodulin-dependent protein kinase, PLC - phospholipase C, PI - phosphoinositides, PC - phosphatidylcholine, IP3 - Inositol trisphosphate, DAG - diacylglycerol,

INS - insulin, CGF - cell growth factor, CK - cytokines, TK - tyrosine kinase. Arrows indicate pathways of intense influence

Another second messenger, cyclic guanosine monophosphate (cGMP), is produced by two guanylyl cyclases: membrane-bound (activated by natriuretic hormones) and cytosolic (soluble), which is activated by the monoxides NO•, CO, and •OH. The latter represent a new class of inorganic regulators with intercellular and intracellular sites of action. cGMP also activates PKG through its dissociation (similar to PKA), and also modulates The activity of other proteins and activates Ion Channels (cGMP-gated channels), which is crucial for light perception by visual receptors.

Table 4.3

Examples of second messengers

Many hormones activate phospholipase C via G-proteins, which generates two messengers from membrane phosphatidylinositides: inositol trisphosphate (IP₃) and diacylglycerol (DAG), and only DAG from phosphatidylcholine. IP₃, by binding to receptors on The endoplasmic reticulum membrane, triggers the release of Ca²⁺ ions into the cytosol. Ca²⁺ ions, acting as an intracellular messenger, along with the protein calmodulin, activate cytosolic Enzymes either directly or via Ca²⁺-calmodulin-dependent protein kinase. The intramembrane messenger DAG activates protein kinase C and itself serves as a precursor for the second messenger arachidonic acid (Table 4.4).

A system of membrane receptors with tyrosine kinase activity (which phosphorylate proteins at tyrosine residues, rather than Serine and Threonine like cytosolic protein kinases). The formation of a hormone (antigen)-receptor complex stimulates the receptor's tyrosine kinase activity, resulting in the phosphorylation of many proteins, including phospholipase C (Fig. 4.17).

The nuclear effects of primary signaling molecules are most commonly associated with the activation of tyrosine kinases and protein kinases C and A. Three Main Mechanisms for the transduction of cytosolic signals into intranuclear ones have been established (Fig. 4.18).

Fig. 4.18. Three pathways of cytosolic signal transduction into intranuclear signals:

TK - tyrosine kinase, TF - Transcription factor, PK - protein kinase, P - phosphate residue, I - inhibitor. → - translocation of the signaling molecule into the nucleus. Dashed lines indicate alternative signaling pathways. Early genes - response within 15-20 min, late genes - within hours and days

All three mechanisms are associated with the protein kinase phosphorylation of regulatory proteins—transcription factors or their precursors. In the first mechanism, typical of the action of Blood serum or cAMP-dependent hormones, activated cytosolic PKs (MAP kinase: mitogen-activated protein kinase) or the active subunit of PK A penetrate the nucleus. In the second mechanism (for growth factors, cytokines, and interferons—antiviral proteins), the signal is transmitted to the nucleus not by the PK itself, but by a protein phosphorylated by it. In the third mechanism, which mediates the effects of cell growth factors, reactive oxygen species, ultraviolet light, and regulates inflammatory and immune processes, a phosphorylated inhibitory subunit is cleaved from the protein transcription factor. The final steps in The regulation of nuclear processes by various hormones (including lipid-soluble ones—Fig. 4.16) are closely related: they involve the interaction of the hormone-receptor complex or a modified transcription factor with regulatory regions of DNA. mRNAs synthesized during the transcription of early genes encode protein products that serve as new transcription factors for late genes. These three mechanisms do not exhaust all levels of nuclear regulation. An increase in Ca²⁺ concentration and other second messengers can regulate Gene Expression at both post-transcriptional and translational levels.

Extracellular signaling molecules, via their respective second messengers, also regulate the primary functions of mitochondria: the Enzymes of the Krebs cycle and the Respiratory Chain of Oxidative Phosphorylation. The pathway of extracellular signal transduction is shown in Fig. 4.19, which illustrates that the primary signal is transduced into an increase in the cytosolic concentration of second messengers—Ca²⁺ and cAMP. For calcium, There is a continuous exchange across The inner mitochondrial membrane (IMM): entry into the matrix driven by the Membrane Potential energy and efflux back in exchange for Na²⁺ (or H⁺) driven by the pH gradient energy. Ca²⁺ ions act directly on mitochondrial enzymes of both the matrix and the IMM. cAMP interacts with the IMM receptor and also penetrates into all mitochondrial compartments, each of which contains protein kinases A. It should be noted that mitochondrial regulation is not limited to four hormones and two second messengers (Fig. 4.19). It is now established that mitochondrial functions are also stimulated by cGMP, protein kinase C, and other signaling molecules.

Fig. 4.19. Transmission of information from signaling molecules to mitochondria:

1 - glucagon, 2 - catecholamines, 3 - vasopressin, 4 - angiotensin II, "+" and "-" - membrane potential across the inner mitochondrial membrane, E - mitochondrial matrix enzymes, other designations are the same as in Figs. 4.16-4.18

Thus, each cell possesses a complex of signal transduction systems that transform all extracellular signals into intracellular messengers, ultimately resulting in the activation of enzyme and channel systems. Signals are transmitted to the nucleus through the translocation of cytosolic protein kinases or activated transcription factors. Signals are transmitted to mitochondria via the translocation of second messengers (Ca²⁺ and cAMP) from the cytosol, which act directly on mitochondrial functional proteins.

The Use of second messengers (Table 4.4) and protein kinase cascades (including membrane tyrosine kinases) allows for a dramatic amplification of various cellular responses to a standard signal. For example, a single receptor molecule activated by a ligand can activate many Gs protein molecules. Each activated G-protein molecule activates an adenylate cyclase molecule. Each adenylate cyclase molecule generates numerous cAMP molecules. Similar processes occur in the inositol phospholipid pathway. As a result, nanomolar (10^-9 mol/L) concentrations of extracellular ligand trigger the generation of second messengers in micromolar (10^-6 mol/L) concentrations. Since these molecules act as allosteric effectors (activating proteins by binding to them and altering their conformation), a single ligand molecule ultimately activates thousands of molecules inside the cell.