Hormonal regulation

regulation of hormones

1. Receptor Mediated Hormonal Regulation By: Hina 2

2. Contents Hormones Mechanism of action of hormones Physiological roles of hormones Site of synthesis of hormones Target sites of horomes 3

3. Hormone Hormones are chemical messengers secreted into blood or extracellular fluid by one cell that affect the functioning of other cells. “ON” “OFF” Target cell Cell origin (Effects) 4

4. Mechanism of action of hormones The ability of a hormone to induce a response in a target cell is usually mediated by a hormone receptor on, or in, the target cell. RECEPTOR Receptors are the sensing elements in system of chemical communication that cordinate cellular function in our body. The binding sites on the target cells are called hormone receptors. 5

5. Types of Hormone Receptors Cell surface receptors G-Protein coupled receptor Kinase linked receptor Intracellular Receptors Nuclear receptor 6

6. Cell surface receptors G-Protein coupled receptor 7

7. G-Protein coupled receptor Adenylate cyclase mediated pathway 8

8. G-Protein coupled receptor Hormone Action using cAMP Second Messenger Glycogen synthase a Glycogen synthase b Protein kinase (Inactive) Protein kinase (Active) Phosphoprotein phosphatase Insulin (+) (+) (+) (+) Glycogen Phosphorylase b Glycogen Phosphorylase a Glycogen Glucose-1-PO4 (+) GLYCOGENOLYSIS Phosphorylase kinase (inactive) Phosphorylase kinase (active) Phospho- protein phosphatase Adenylate cyclase ATP cAMP (+) (-) (+) Muscles Liver Adenylate cyclase mediated pathway 9

9. G-Protein coupled receptor P hospholipase mediated pathway Receptor DAG IP 3 Ca ++ Protein kinase C Phosphoproteins Proteins Physiologic responses Ca ++ -Calmodulin Calmodulin kinases (+) (+) GDP GTP Phospholipase C GTP GDP (+) PIP 2 Hormone Action using DAG, IP 3 and Ca ++ as Second Messengers 10

10. Mechanism of Tyrosine Kinase Receptors When hormone binds to the extracellular domain the receptors aggregate Kinase linked receptor 11

11. When the receptors aggregate, the tyrosine kinase domains phosphorylate the C terminal tyrosine residues Mechanism of Tyrosine Kinase Receptors 12

12. This phosphorylation produces binding sites for proteins with SH2 domains. GRB2 is one of these proteins. GRB2, with SOS bound to it, then binds to the receptor complex. This causes the activation of SOS. Mechanism of Tyrosine Kinase Receptors 13

13. SOS is a guanyl nucleotide-release protein (GNRP). When this is activated, it causes certain G proteins to release GDP and exchange it for GTP. Ras is one of these proteins. When ras has GTP bound to it, it becomes active. Mechanism of Tyrosine Kinase Receptors 14

14. Activated ras then causes the activation of a cellular kinase called raf-1 Mechanism of Tyrosine Kinase Receptors 15

15. Raf-1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK Mechanism of Tyrosine Kinase Receptors 16

16. Activated MEK then phosphorylates another protein kinase called MAPK causing its activation. This series of phosphylating activations is called a kinase cascade. It results in amplification of the signal Mechanism of Tyrosine Kinase Receptors 17

17. Among the final targets of the kinase cascade are transcriptions factors ( fos and jun showed here). Phosphorylation of these proteins causes them to become active and bind to the DNA, causing changes in gene transcription Mechanism of Tyrosine Kinase Receptors 18

18. Hormone Metabolism JACK/STAT Pathway ES utilized by Growth hormone, Prolactin, EPO, cytokines… Regulates transcription Nucleus Dimerization X = SHC GRB2 PLC  PI-3K GAP JAK P JAK P P P P P STATs X SH2 P P ) ( JAK P JAK P P P P P JAK JAK Kinase linked receptor 19

19. Intracellular ( nu clear) receptor mediated pathway Basic Structure of nuclear receptor Hormone-bindind domain DNA-binding domain Transcription-activating domain 20

20. Hormones that can cross the membrane (e.g. steroid hormones) bind to the receptor inside the cell, at the cytoplasm, or they will enter the nucleus and bind nucleus and bind to the receptor at the nucleus and initiate transcription Intracellular ( nu clear) receptor mediated pathway 21

21. The signal pathway by steroid hormones N uclear receptor mediated pathway 22

22. The signal pathway by steroid hormones 23

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25. Insulin Pancreas Controls blood-sugar level and storage of glycogen. Glucagon Pancreas Stimulates conversion of glycogen to glucose; raises blood sugar level. Oxytocin Pituitary gland Stimulates contraction of the uterine muscles and secretion of milk by the mammary glands. Vasopressin Pituitary gland Controls water excretion by the kidneys; stimulates contraction of the blood vessels. Growth hormone Pituitary gland Stimulates growth. Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which,in turn,releases hormone (ACTH) several steroid hormones. Prolactin Pituitary gland Stimulates milk production by the mammary glands after birth of baby. Epinephrine Adrenal glands Stimulates rise in blood pressure, acceleration of heartbeat, decreased secretion of insulin, and increased blood sugar. Hormone Source Principal functions Physiological role of Hormones 26

26. Cortisone Adrenal glands Helps control carbohydrate metabolism, salt and water balance, formation and storage of glycogen. Thyroxine & Thyroid gland Increases the metabolic rate of carbohydrates Triiodothyronine and proteins. Calcitonin Thyroid gland Prevents the rise of calcium and phosphate in the body. Parathyroid Parathyroid gland Regulates the metabolism of calcium and phosphate in hormone in the body. Gastrin Stomach Stimulates secretion of gastric juice. Secretin Duodenum Stimulates secretion of pancreatic juice. Estrogen Ovaries Stimulates development and maintenance of female sexual characteristics. Progesterone Ovaries Stimulates female sexual characteristics and maintains pregnancy. Testosterone Testes Stimulates development and maintenance of male sexual characteristics. Hormone Source Principal functions 27

27. Types of Hormones Catecholamines and Thyroid Hormones Small and derived from amino acids (epinephrine, thryoxine .) Steroid Hormones and Vitamin D Relatively small and derived from cholesterol Prostaglandin's Relatively small and derived from fatty acids Proteins or Polypeptides Relatively large and derived from translation of hormone specific mRNA (growth hormone, insulin) Site of synthesis of various hormones 28

28. Thyroid Hormones Synthesized solely in the thyroid gland ( T4 ; 3’,5’,3,5-L-tetra-iodothyronine). Majority of the active form, T3 (3’,3,5-L-tri-iodothyronine), is produced in the peripheral tissues through deiodination of T4 . Thyroid gland cells concentrates iodine for thyroid hormone synthesis. Iodine is attached to tyrosine residues on a protein, termed thyroglobulin . Tyrosine residues are then coupled together to yield thyronines . Proteolytic digestion of thyroglobulin then yields T4 and T3 in a 10:1 ratio. Helps in the metabolism of sugars . The half life of T4 is 7 days and that of T3 is 1 day. 29

29. Steroid Hormones Produced in the adrenals, ovaries, testes, and placenta. Derived from cholesterol. Enzymes in the various glands control the final product. For example, cytochrome P450c11 which is located in the adrencortical cells, is involved in coritsol production. This enzyme is lacking in the gonads, that do not produce cortisol or aldosterone . Gonads, however, can produce dihydroxytestosterone , estradiol , or progesterone depending upon the enzymes present in the gonadal tissue. Over 50 different steroid metabolites have been described. 30

30. Catecholamines Are synthesized in nervous tissues from which the adrenal medulla is derived. Adrenal medulla is the major source for circulating epinephrine. Synthesized from tyrosine which is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylases . Subsequent conversions to dopamine and then to nor epinephrine which is released by most catecholamine-producing cells of the body. In the adrenal medulla and a few other tissue, nor epinephrine is converted to epinephrine. The half life is 1-2 minutes . 31

31. Prostaglandins and Leukotrienes They can be produced by most cells depending upon lipid and enzyme content of the cells. Arachidonic acid , which is derived from lipid metabolism, is the precursor compound. Depending upon the lipoxygenase present in the cell, either, HETE, prostaglandin (G2) or leukotrienes Cyclooxygenase (involved in PGG 2 synthesis) is widely distributed throughout the body and is inhibited by aspirin, indomethacin , and other nonsteroidal and anti-inflammatory agents. The half-life is a few seconds . 32

32. Target Sites of hormones Target cells: Cells that respond to a specific hormone Can be found anywhere in the body All target cells have receptors that detect specific hormones Ex: Thyroid hurmone act on almost all cells of the body to increase rate of metabolism Hormones specifically affect or alter the activities of the responsive tissue (target tissue). 33

33. 1. Endocrine Chemicals act on distant cells via the bloodstream Ex: thyroxine , sex hormones 2. Paracrine Chemicals act on the surrounding cells or neighboring tissues without entering the blood Ex: GIT hormones 3. Autocrine Chemicals act on the cell that produce it Ex : nitric oxide 4. Neuroendocrine Synthesize & release into blood stream by nerves signals between neurons Ex: neurotransmitters ( Ach, dopamine ) Actions of hormones 34

34. Endocrine Blood vessel Distant target cells Hormone secretion into blood by endocrine gland Paracrine Secretory cell Adjacent target cell Autocrine Target sites on same cell Receptor Hormone or other extra cellular signal 35

35. Second target mechanism By receptors and target cells The receptor and target cell action depends on two terms broadly Agonist Antagonist 36

36. Agonists Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect Natural hormones are themselves agonists. For a given receptor, different agonists can have different potencies 37

37. Antagonist Antagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signalling events. They don't themselves perform useful work, but block the activities of those that do have the capacity to contribute. Hormone antagonists are widely used as drugs. 38

38. Antagonist to Use Growth Hormone Acromegaly , Diabetes Progesterone Contraceptive, abortion Glucocorticoid Spontaneous Cushing’s Syndrome Mineralo -corticoid Primary and secondary mineralocorticoid excess Androgen Prostate cancer Estrogen Breast cancer GnRH Prostate cancer Adrenrgic Hypertension, hyperthyroidism Prostaglandin Acute and chronic inflammatory disease Examples of hormone antagonist used in therapy 39

39. When you do not succeed in taking giant steps on the road to your goal, be satisfied with little steps, and wait patiently till the time that you are able to run, or better still, to fly. Be satisfied to be a little bee in the hive who will soon become a big bee capable of making honey… Thank you … 40 Any Question????