TRANSMEMBRANE TRANSDUCTION

OF THE HORMONAL SIGNAL

Hormones are substances of organic nature, which are produced in the specialized cells of the endocrine glands, enter into the bloodstream and have a regulating effect on the metabolism and physiological functions. The specific characteristics of the biological action of hormones: hormones exert their biological effects in very small concentrations (from 10^-6 to 10^-12 M); the hormonal effect is realized through protein receptors and intracellular second messengers; hormones increase the rate of enzyme synthesis de novo or change the velosity of enzymatic catalysis; the hormones effect in the whole organism is determined to some extent by controlling influence of the CNS.

Modern classification of hormones is based on their chemical nature.

1. Peptide and protein hormones include from 3 to 250 or more amino acid residues, for example, hormone of the hypothalamus and pituitary gland (growth hormone, corticotropin and others), and pancreatic hormones (insulin, glucagon).

2. Amino acid derivatives. These are adrenaline and thyroid hormones.

Hormones of these two groups are highly soluble in water.

3. Steroid hormones. All of them are formed from cholesterol. These are corticosteroids, sex hormones (estrogens and androgens), hormonal form of vitamin D. Steroid hormones are lipophilic substances, easily penetrating the cell membrane.

4. Eicosanoids are hormone-like substances that have a local effect. They are derived from polyunsaturated fatty acid – arachidonic acid.

Cell membranes due to the presence of specific receptors receive signals from the environment (for example, molecules of hormones, called primary messengers or intermediaries). The first stage of the hormone action on the target cell is its binding to the receptor, and then the signal is transmitted into the cell. By its chemical nature, almost all the receptors of biologically active substances are glycoproteins. A common property of all receptors is their high specificity towards one specific hormone.

Adenylatecyclase messenger system is the most studied system(Fig. 17). It involves: 1) hormone receptor, and 2) the enzyme adenylyl cyclase, and 3) G- protein, and 4) cAMP -dependent protein kinase 5) phosphodiesterase.

Fig. 17. Adenylatecyclase messenger system.

The molecules of the protein hormones (insulin), hydrophilic molecules (adrenaline) cannot pass through the cell membrane. Their receptors are located on the membrane. Binding of hormone ( the primary messenger ) to the receptor leads to structural changes in the receptor intracellular domain. It provides interaction of the receptor with GTP-binding protein (G-protein). G-protein is a mixture of two types of proteins: active G_s (from the Eng. stimulatory) and inhibitory G_i. They have three different subunits (α, β and γ ). The function of G-protein is carrying out a hormonal signal at the plasma membrane. Hormone-receptor complex transforms G_s-protein in the activated state. It is activated by dissotiation of G-protein subunits. The active G-protein activates adenylate cyclase. Adenylate cyclase is almost inactive in the absence of G-protein.

Adenylate cyclase is an integral plasma membrane protein and its active site is oriented toward the cytoplasm. Adenylate cyclase catalyzes the reaction of synthesis of cAMP from ATP. cAMP is a second messenger.

Under the action of cAMP inactive protein kinase turnes into active form. This enzyme catalyzes the phosphorylation of intracellular enzymes or target proteins, changing their activity. This reaction goes with the participation of serine, threonine, tyrosine OH-groups. Phosphorylation and dephosphorylation of proteins with the participation of protein kinases is a common fundamental mechanism of secondary messengers within the cell.

Phosphodiesterase causes the breakdown of cAMP and thereby terminates the hormonal signal.

Steroid and thyroid hormones are lipophilic and can easily pass through cell membranes. The receptors of these substances are in the cytosol or nucleus of the cell ( intracellular receptors ).

Complex of hormone with a receptor is formed in the cytosol, and then enters the nucleus. Hormone-receptor complex passes into the nucleus and interacts with a regulatory nucleotide sequence in DNA. Accordingly, the rate of transcription of structural genes and the rate of translation are changed. Consequently, the amount of proteins, which may affect the metabolism and functional state of the cell, is also changed (Fig. 18).

Fig. 18. Hormonal signals transduction through intracellular receptors.

Complex " hormone - receptor" may be formed directly in the nucleus. Thyroid hormone receptors are always associated with DNA.

Hormones provide a communication (information exchange) between different cells and organs. As a result of these mechanisms, coordination of metabolism and functions of different cells and organs and adequate reaction to changes in the environment are achieved.

The role of extracellular signals not only hormones can performe, but also a number of other substances - cytokines, biogenic amines, neurotransmitters, etc.

Test Questions

1. What is the transmembrane transfer of signals?

2. Which compounds can act as primary messengers, second messengers?

3. Describe the main parts and the mechanism of action of adenylatecyclase messenger system.

4. List the major types of regulation of enzyme activity in the cell.

 

6. INTRODUCTION TO METABOLISM

Metabolism (from the Greek " transformation, change" ) is a set of chemical reactions in living cells, providing growth, development and activity of the body and life in general.

Metabolism consists of two opposing simultaneous processes.

Catabolism includes reactions associated with the breakdown of substances, their oxidation and elimination of waste products from the body. Catabolic reactions are exergonic (give energy).

The organelles of catabolic system are mitochondria, lysosomes, peroxisomes.

(Peroxisomes are cellular organelles, which are carrying out the oxidation of fatty acids, the synthesis of bile acids, cholesterol, etc. Glioxysomes are a kind of peroxisomes, in which the oxidation of glyoxylate cycle and the Krebs cycle going on.)

Anabolism integrates all reactions associated with the synthesis of essential substances, their assimilation and use for growth, development and functioning of the body. Anabolic reactions are usually endergonic (energy consuming). The organelles of anabolic system are endoplasmic reticulum and ribosomes, Golgi apparatus.

Metabolites are products of metabolism of some compounds.

Stages of metabolism:

1. Intake of substances in the body (breathing, eating, digestion).

By digestion polymers (starch, proteins, fats) break down to monomers (amino acids, glucose, etc.), which pass into the blood.

2. Intracellular metabolism (intermediate exchange) is a set of metabolic pathways.

Metabolic pathways are the consistent transformation of one substance into another, of one metabolite into another.

There is usually a reaction in the pathway with a slower rate than others. It is the rate-limiting stage ( reaction ). It determines the overall rate of conversion of a substance into a final product of the metabolic chain.

The enzyme that catalyzes the rate-limiting reaction is called regulatory one.

The reactions of metabolism are mainly reversible. Their direction is determined by consumption or removing of the product.

Under constant conditions, the concentration of several metabolites in cells and extracellular fluids is constant. In diseases, the steady-state concentrations of metabolites are specifically changed. It is the base of biochemical methods of laboratory diagnostics of diseases.

 

6.1. STAGES OF CATABOLISM

Stages of catabolism

I. Hydrolytic stage. Proteins, fats and carbohydrates are broken down into the corresponding monomers under the influence of hydrolases in the digestive tract.

II. Specific pathways of catabolism. Monomers of major nutrients (with the participation of enzymes that are specific to each class of substances) are transformed into two metabolites - pyruvic acid and acetyl-CoA. At this stage, 1/3 energy of nutrients is released.

Acetyl-CoA (acetyl coenzyme A) is the energy-rich product of condensation of coenzyme A with acetic acid. It includes pantothenic acid. Coenzyme A is in the free state in the cell and interacts with the enzyme at the moment of reaction with the substrate.

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