1st Year MB/BDS Plenary Lecture What is a Hormone?

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1 1st Year MB/BDS Plenary Lecture What is a Hormone?

2 The term hormone (from the Greek for I arouse to activity or I excite) was first used by Starling in Hormones are just one type of first (or primary) messenger - other first messengers include the neurotransmitters and the local mediators. Hormones are familiar to the general public, due to the widespread pharmacological use and abuse of steroid hormones for diverse purposes including contraception and body building.

3 Hormones can be classified according to the distance over which they act. Endocrine hormones act on cells distant from the site of their secretion. These hormones, like insulin and adrenaline are synthesized and released into the bloodstream by specialized ductless endocrine glands.

4 Insulin is secreted from islet cells in the pancreas. In insulin-dependent diabetes an autoimmune response selectively destroys these islet cells. Typically, the disease develops over several years as the immune system slowly destroys islet cells. Only when > 80% of these cells are destroyed do the classic symptoms of diabetes emerge.

5 Paracrine (from the Greek para - beside) hormones (also known as local mediators) act only on cells close to the cell that released them. Local mediators differ from neurotransmitters in that they are released in a non-directional manner into the extracellular space, rather than into the defined space of the synaptic cleft. Prostaglandins, histamine and many polypeptide growth factors are examples of this class.

6 The use of aspirin as an analgesic (pain-relieving), anti-pyretic (fever-reducing) and anti-inflammatory agent is widespread. Aspirin, like other nonsteroidal anti-infammatory drugs (NSAIDs) inhibits the synthesis of prostaglandin from arachidonic acid.

7 Histamine Histamine is derived from the amino acid histidine and is released by mast cells which are activated at the site of injury or infection. One of its effects is to cause blood vessels to become leaky. This accounts for the redness, swelling and pain at the site of a local infection. The beneficial aspect of this is that components of the immune system (antibodies, complement, lymphocytes and phagocytes) gain access to the site of infection. Histamine has many other effects and is involved in the allergic response to pollen (hay fever).

8 Autocrine hormones act on the same cell that released them. Interleukin-2, which stimulates T cell proliferation, is an example.

9 Cytotoxic T cell. Macrophage Interleukin-2 production T cells that bind to a macrophage displaying an antigen are induced to propagate (clonal selection). This process is enhanced by the T cells auto-stimulatory secretion of interleukin-2. T cells only express interleukin-2 receptors while bound to a macrophage thereby preventing unlimited T cell proliferation.

10 Neurotransmitters Primary messengers released by nerve cells. Nerve cells can be thought of as being like endocrine cells which have a long extension (axon) by means of which the primary messenger is released very close to the target cell. The nerve impulse travels down the axon to signal the release of neurotransmitter from storage vesicles. Include compounds like noradrenaline also a hormone (released, with adrenaline, from the adrenal gland).

11 Biochemical communications are not limited to intracellular and intercellular signals. Many organisms release pheromones that alter the behaviour of other organisms of the same species in much the same way as hormones. Pheromones are common sexual attractants. The complex social interactions of species such as ants are dependent on pheromones.

12 The human endocrine system enables the body to: Maintain homeostasis e.g. insulin and glucagon maintain the blood glucose level within tight limits - irrespective of food intake. Respond to a wide variety of external stimuli - such as the use of adrenaline and noradrenaline in the preparation for fight or flight. Follow various cyclic and developmental programs sex hormones regulate sexual differentiation, maturation, the menstrual cycle and pregnancy.

13 Only those cells with specific receptors for a given hormone will respond to its presence even though nearby cells may also be exposed to the hormone. The insulin receptor i.e. hormonal messages are specifically addressed. The β-adrenergic receptor

14 What happens after a hormone binds a cell-surface receptor?

15 Most hormones are either polypeptides, amino acid derivatives or steroids. Insulin is a polypeptide hormone, synthesized from a precursor proinsulin. The C chain of proinsulin is proteolytically cleaved from between the A and B chains to form the mature, active hormone.

16 Adrenaline (R=CH 3 ) and noradrenaline (R=H). Isoproterenol - a β- adrenergic agonist, will specifically bind and stimulate the β-adrenergic receptor. Propranolol a β-adrenergic antagonist, will specifically bind and block the β- adrenergic receptor (A β- blocker).

17 The steroid hormones are all derived from cholesterol.

18 Progesterone, a progestagen, synthesized in the corpus luteum prepares the lining of the uterus for implantation of an ovum and is essential for maintenance of pregnancy.

19 Androgens (e.g. testosterone), synthesised in the testes, are responsible for the development of male secondary sex characteristics. Estrogens, synthesized in the ovaries, are required for the development of female secondary sex characteristics. Estrogens, along with progesterone, also participate in the ovarian cycle.

20 Glucocorticoids (e.g. cortisol) stimulate gluconeogenesis and enhance the breakdown of fat and protein and inhibit the inflammatory response they enable animals to respond to stress. Mineralocorticoids (e.g. aldosterone) act on the kidneys to stimulate sodium re-uptake which leads to an increase in blood pressure. These hormones are synthesised in the adrenal cortex.

21 Steroid hormones are all lipid-soluble i.e. in contrast to polypeptide and other hormones they will easily pass through target cell plasma membranes. Steroid hormones bind and activate receptor molecules within target cells. The receptor molecules are all transcription factors that regulate gene expression. That different classes of steroid molecule exert such distinct physiological effects is due to small structural differences that allow interactions with distinct receptor molecules (transcription factors).

22 This sequence is symmetrical; consequently, the receptors bind as dimers. Estrogen action When inside a cell, estrogens bind to highly specific, soluble receptor proteins. Estrogen receptors are members of a large family of proteins (the nuclear hormone receptors) that act as receptors for a wide range of hydrophobic molecules, including other steroid hormones, thyroid hormones and retinoids. On binding estrogen, the steroid/receptor complex modifies the expression of particular genes by binding to specific control elements in promoter DNA. Estrogen receptors bind to specific DNA sites estrogen response elements or EREs that contain the consensus sequence: 5 -AGGTCANNNTGACCT-3

23 Estrogen binding to the receptor leads to a substantial structural rearrangement in the protein. Hormone binding does not greatly alter the ability of the receptor to bind DNA. Co-activator proteins bind to the receptor - but only in the presence of the hormone. The resulting transcription complex stimulates gene expression.

24 Co-activator Recruitment

25 Steroid hormone receptors as targets for drugs Athletes sometimes take natural and synthetic agonists ( anabolic steroids ) of the androgen receptor the androgen receptor stimulates the expression of genes that enhance the development of muscle mass. In men, excessive use leads to a decrease in the secretion of testosterone which may in turn lead to testicular atrophy or breast enlargement. In women, excess testosterone causes a decrease in ovulation and estrogen secretion, breast regression and growth of facial hair.

26 Some important drugs are antagonists of the estrogen receptor. Tamoxifen is used in the treatment (and prevention) of breast cancer, because some breast tumours rely on estrogenmediated pathways for growth. These antagonists block the binding of co-activators to the receptor and therefore inhibit activation of gene expression. Tamoxifen

27 Summary Hormones are just one example of primary messenger molecule. Only those cells with specific receptors for a given hormone will respond to its presence. Most hormones are either polypeptides, amino acid derivatives or steroids. When inside a cell, steroid hormones bind to highly specific, soluble receptor proteins. The steroid/receptor protein complex modifies the expression of particular genes by binding to specific control elements in promoter DNA. Some important drugs are antagonists of the estrogen receptor.

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