HORMONES (Biomedical Importance)

Transcription

1 hormones

2 HORMONES (Biomedical Importance) Hormones are the chemical messengers of the body. They are defined as organic substances secreted into blood stream to control the metabolic and biological activities. Hormonoids (tissue hormones) compounds that are produced not in glands but in different tissues and regulate metabolic processes on the local level, but some of them (serotonin, acetylcholine) enters blood and regulate processes on the organism level. hormones are involved in transmission of information from one tissue to another and from cell to cell. These substances are produced in small amounts and are highly specific in their functions. They are delivered directly to the blood and are carried by the blood to various target organs where these exert physiological effect and control metabolic activities. Frequently their site of action is away from their origin. in one part of the body, enters the circulation and is carried to distant target organs and tissues to modify their structures and functions. to modify their structures and functions It is a chemical substance which is produced in one part of the body, enters the circulation and is

3 The deficiency of any hormones leads to a particular disease, which can be cured by administration of that hormones. a chemical substance which is produced in one part of the a chemical substance which is produced Hormones are released continuously or in short bursts, amount and frequency can vary. Circulating hormones are transported by blood in solution or attached to plasma proteins. Local hormones remain in interstitial fluid and act on nearby cells. Hormones produce slower response than nervous system but longer lasting effects. Hormones are inactivated by liver & excreted by kidneys. Functions: Stimulate synthesis of enzymes or structural proteins. Change rate of synthesis. Inactivate or activate existing enzymes or protein channels.

4 Transport of hormones in blood Protein and peptide nature in free state Steroid hormones and hormones of thyroid gland bound with alpha-globulins or albumins Catecholamines in free state or bound with albumins, sulphates or glucuronic acid Reach the target organs Cells have the specific receptors to certain hormone

5 Target cells target cell include any cell in which the hormone (ligand) binds to its receptor, whether or not a biochemical or physiologic response has yet been determined. A target cell respond to hormone with a sequence of events. 1) Receptores activation by the input signal (the hormone ) 2) Conversion of the input signal into a biochemical change in the cell. 3) Response of the cell ( contraction, secretion, transport, synthesis, breakdown). these cells are affected by hormone and respond in unique fashion: Cells have specific receptors on membrane or in cell that respond to hormone Can have receptors for several different hormones Number of active receptors can change ( Down-regulation or Upregulation)

6 Target cells sensitive to several hormones may show interactive effects. Permissive effects - first hormone enhances the effect of a later hormone action: Thyroid hormone increases the effect of epinephrine on breakdown of triglycerides in adipocytes. Integrative effects - hormones produce complementary effects on different tissues: PTH and calcitriol increase ECF calcium Synergistic effects - two hormones acting together have a greater effect than the sum of the effects of each hormone acting independently. Both FSH and estrogen necessary for normal oocyte development. Antagonistic effects - one hormone opposes the action of the other hormone. Insulin and glucagon.

7 Several factors determine the response of a target cell to a hormone. These can be thought of in two general ways: Determinants of the Concentration of a Hormone at the Target Cell The rate of synthesis and secretion of the hormones. The proximity of the target cell to the hormone source (dilution effect). The dissociation constants of the hormone with specific plasma transport proteins (if any). The conversion of inactive or sub optimally active forms of the hormone into the fully active form. The rate of clearance from plasma by other tissues or by digestion, metabolism, or excretion

8 Determinants of the Target Cell Response 1.The number, relative activity, and state of occupancy of the specific receptors on the plasma membrane or in the cytoplasm or nucleus. 2. The metabolism (activation or inactivation) of the hormone in the target cell. 3. Up- or down-regulation of the receptor consequent to the interaction with the ligand. prolonged high levels may decrease the number of receptors and reduce the response in target cells, a process called down regulation Continuous low levels of a hormone, or another stimulating signal may increase the number of receptors and the sensitivity of the target cell, a process called up regulation.

9 HORMONE RECEPTORS ARE OF CENTRAL IMPORTANCE Receptors :are proteins, to which hormones bind. They are present in cell membranes, cytoplasm or in the interior of the cell. Water soluble hormones cannot diffuse into cell, they bind to receptors in the plasma membrane Lipid soluble hormones diffuse into cell where they bind with intracellular receptors. Domains present on the receptors All receptors have two functional domains: 1. Recognition domain: it binds the hormone 2. Coupling domain: it generates a signal that couples the hormone recognition to some intracellular function. Coupling means signal transduction..

10 Signal Amplification Via 2 nd Messenger Pathways Initial signal is in the form of hormone which acts as ligand whose concentration is just one/per receptor. The hormonal response has got multiple steps, and each step multiplies the signal (cascading effect) that finally leading to million fold amplification, i.e. one hormone molecule mediating its effect through million of molecules. This process is known as signal amplification. Transduction: The biochemical mechanism(s) that allow the transfer of information between an occupied hormone-receptor & the molecules within the cell that result in production of a cellular response. Ligand Receptor Transducer Amplifiers

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12 Classification of hormones Hormones are classified on the basis of: (i) Their structure. (ii) Their site of activity in the cell. Hormones are classified according to their structures into:

13 Classification of hormones Steroid hormones 1. Sex hormones - are divided into 2 groups (i) Male sex hormones or Androgens (testosterone) (ii) Female sex hormones- Estrogens/Progesterons 2. Hormones of Adrenal Cortex mineralocorticoids /glucocorticoids Non steroid hormones Peptide hormonese.g. all hypothalamic, anterior pituitary, digestive hormones Amino acid derivatives Amines - simplest form, derived from tyrosine or tryptophan e.g. Thyroid hormone, dopamine, epinephrine, melatonin Prostaglandins and cytokines

14 Classification of Hormones by Mechanism of Action I. Hormones that bind to intracellular receptors Retinoic acid & Thyroid hormones (T3 and T4 ) II. Hormones that bind to cell surface receptors A. The second messenger is camp Follicle-stimulating hormone (FSH), Glucagon,Thyroid-stimulating hormone (TSH). B. The second messenger is cgmp Atrial natriuretic factor, Nitric oxide C. The second messenger is calcium or phosphatidyl inositols (or both) Angiotensin II, Antidiuretic hormone (vasopressin). D. The second messenger is a kinase or phosphatase cascade Adiponectin,Erythropoietin,Insulin, Leptin,

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16 Steroid hormone action receptors typically located inside cells most of them located in the nucleus.each receptors has two binding sites : a. One site binds the hormone b. One side bind to DNA 1.When the hormone Diffuse through the membrane 2. Binds to the receptor. The receptor change their shape this activate the receptor and cause the chaperon protein to dissociate from the complex. 3. The hormone-receptors complex then enters the nucleus and binds to a particular sequence on the DNA. This sequence is called hormone response element (HRE). Thus the gene begins to be transcribed and translated, and a new protein appears in the cell and assumes its normal function within it (or gets secreted).

17 In contrast hormones such as: Thyroid and Retinoids go directly into the nucleus. Their receptor is already bound to HRE, but along with a co repressor protein which fails to activate transcription. The association of the ligand with the receptor results in the dissociation of the co repressor. Now this receptor- ligand complex can bind co activator proteins and transcription begins. The action of nuclear receptors is slow, as it takes some hours for the whole process to occur. The effect is long-lasting (or even permanent). This type of process is important in development, differentiation and maturation of cells, e.g. gametes (eggs and sperm cells).

18 Cell Surface Receptors There are three types of cell surface receptors: 1. Ion channel receptors, 2. Trans membrane receptors. 3. Receptors that are kinases or bind kinases. 1. Ion channel receptors: When a signaling molecule binds to an ion channel on the outside of the cell, this triggers the change of the 3D conformation of the protein and the channel opens, allowing the ions to move in or out of the cell following their electrical gradients and thus altering the polarization of the cell membrane.

19 2. Trans membrane receptors. Transmembrane proteins include G proteinlinked receptors When the hormone bind to the receptor.the receptor change its shape and activate G protein. It releases GDP and bind GTP. the activated GTP activated the enzyme adenylate cyclase. adenylate cyclase catalyze the conversion of ATP to c AMP. c AMP is a second messenger. The hormone is the first messenger. c AMP activates the intracellular enzyme, protein kinase A, which can phosphorylate many other proteins. (epinephrine, FSH, TSH)

20 3. Receptors that are kinases or bind kinases. Tyrosine Kinase Second Messenger Systems (insulin) The hormone binds to domains exposed on the cell's surface. resulting in a conformational change that activates kinase domains located in the cytoplasmic regions of the receptor. In many cases, the receptor phosphorylates itself as part of the kinase activation process. The activated receptor phosphorylates a variety of intracellular targets, many of which are enzymes that become activated or are inactivated upon phosphorylation

21 Clinical applications of hormones Distribution of estrogens and progesterone in contraceptives (P pills) is world-wide. Estrogens are widely used to relieve postmenopausal discomfort. Females with osteoporosis are treated with calcitonin, because calcitonin inhibits osteoclastic bone resorption. Insulin is a lifesaver for diabetics, and it is produced and distributed as pure human insulin. In the affluent areas of the world many women deliver their babies following an oxytocin infusion. estrogens and gonadotropins are used in treatment of sterility and menstrual disturbances. Huggins received the Nobel Prize in 1966 for the introduction of a new form of cancer therapy in which sex hormones are used to retard their growth. He used androgens for breast cancer and estrogens for prostate cancer.