Endocrine System

1. Endocrine System Huiping Wang (王会平), PhD Department of Physiology Rm C516, Block C, Research Building, School of Medicine Tel: 88208252 Email: wanghuiping@zju.edu.cn

2. RECOMMENDED TEXTBOOK:Widmaier EP, Raff H, Strang KT (2006) Vander’s Human Physiology: The Mechanisms of Body Function, Tenth Edition. McGraw-Hill. • SUPPLEMENTARY READING:Stephan Sanders (2003) Endocrine and Reproductive systems, Second Edition. Mosby. • COURSE WEBSITERS:http://www.endocrineweb.com/ http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/index.html http://medical.physiology.uab.edu/cardio.htm http://www.mhhe.com/biosci/ap/foxhumphys/student/olc/index.htm

3. Endocrine System • General Principles of Endocrine Physiology • Hypothalamus and pituitary gland • Thyroid gland • Endocrine Regulation of Calcium and Phosphate Metabolism • Adrenal gland • Pancreatic hormones

4. General Principles of Endocrine Physiology

5. Outline Endocrine system and Hormone Hormone types Hormone synthesis, storage, release, transport, clearance and action modes Characteristics of hormones Regulation of Hormone Secretion Mechanisms of hormone action

6. Endocrine System • One of the two major communication systems in the body • Have much longer delays • Last for much greater lengths of time • Integrate stimuli and responses to changes in external and internal environment • crucial to coordinated functions of highly differentiated cells, tissues and organs

7. Endocrine gland (ductless) is a group of cellsthat produce and secret a hormone Endocrine Glands Hypothalamus Pituitary (Anterior and Posterior) Thyroid / Parathyroid Endocrine Pancreas (islets) Adrenal Cortex and Medulla Gonad (Ovary and Testis)

8. Endocrine System • The endocrine system broadcasts its hormonal messages to target cells by secretion into blood and extracellular fluid. Like a radio broadcast, it requires a receiver to get the message - in the case of endocrine messages, cells must bear a receptor for the hormone being broadcast in order to respond.

9. What is a hormone? • Chemical messengersynthesized by specific endocrine cells in response to certain stimuli and secreted into the blood • Travel via the circulation to affect one or moregroups of different cells (target cells) to elicit a physiologicalresponse Hormones are primarily informationtransferring molecules

13. Types of Hormones

14. Synthesis of peptide hormones NUCLEUS The DNA code is “transcribed” into mRNA. RIBOSOMES The mRNA is “translated” to give instructions for proteins synthesis.

16. Typical synthesis of peptide hormones • Preprohormones- larger hormones produced on the ribosomes of the endocrine cells • Prohormones- cleavage of preprohormones by proteolytic enzymes in rER • Prohormones- packaged into secretory vesicles by the Golgi apparatus • Prohormones- cleaved to give active hormone and pro-fragments pre-pro-insulin pro-insulin insulin

17. Synthesis of steroid hormones

18. Hormone Storage and Release • Thyroid and steroid hormones • Not stored as secretory granules • Transferring through plasma membrane • Protein and catecholamine hormones • Stored as secretory granules • Released by exocytosis

19. Hormones are not secreted at auniform rate • In a pulsatile pattern • Diurnal (circadian) rhythm: • linked to sleep-wake cycles (cortisol, growth hormone) • Be aware of the pulsatile nature and rhythmic pattern of hormone secretion when relating the serum hormone measurements to normal values

20. Hormones are not secreted at auniform rate • Rhythmic secretion • Cyclic • oestrogen, progesterone, LH

21. Modes of Action • Endocrine – transmission of asignal from a classicendocrine cell throughbloodstream to a distant targetcell e.g. testosterone • Neurocrine – hormone isreleased from a neuron downits axon and then travels viathe bloodstream to target cell • Paracrine - hormone acts onadjacent cells e.g. histamine released at site of injury to constrict blood vessel walls and stop bleeding • Autocrine – hormone isreleased and acts on the cellthat secreted it.e.g. norepinephrine itself inhibits further release by that cellin the adrenal medulla

22. A secretion may have several sites of action simultaneously Example: • Norepinephrine - Autocrine action causes negative feedback on secretion. - Simultaneously, endocrine action causes respiration rate to increase, peripheral blood vessels to constrict, etc.

23. Hormone Transport • Peptides and catecholamine • water soluble • dissolve in blood • circulate in blood mainly in free form • Steroid and thyroid hormones • circulate in blood mainly bound to plasma proteins • the free form is biologically active • the greater binding, the longer half-life

24. Hormone Clearance • The half-life of a hormone in blood is the period of time needed for its concentration to be reduced by half. • Free: min • Binding: mins, hrs, days • e.g. T4 (6 days); Insulin (0.006 days) • Hormone concentration in blood is determined by • secretion rate • clearance rate • Ways of Clearance • target cell uptake • metabolic degradation • urinary or biliary excretion

25. The “metabolic fate” of a given hormone molecule in the blood

26. Characteristics of Hormones • Regulates rate of reaction • Do not initiate • Very specific • Amplification effect • Present in very small quantity • pg/mL ~ g/mL

27. Characteristics of Hormones • Interaction between hormones • Synergistic action • Antagonistic action • Permissive action • Hormone A must be present for the full strength of hormone B’s effect. • Up-regulation of one hormone’s receptors by another hormone • the facilitation of the action of one hormone by another • e.g. the ability of TH to “permit” epinephrine-induced release of fatty acids from adipose tissue cells (TH causes an  no. of epinephrine receptors on the cell)

28. Regulation of Hormone Secretion Three types of inputs to endocrine cells that stimulate or inhibit hormone secretion.

29. Regulation of Hormone Secretion • Negative feedback • Most common • Occurs when a hormone produces a biologic effect that, on attaining sufficient magnitude, inhibits further secretion • Positive feedback • Less common • Amplify the initial biological effect of the hormone

30. Negative Feedback • Characteristic of control systems in which system’s response opposes the original change in the system. • Hormone itselffeeds back to inhibit its own synthesis. • Regulated product (metabolite) feeds back to inhibit hormone synthesis. • Important for homeostatic control. • Example: Control of blood glucose by insulin

32. Positive Feedback • Characteristic of control systems in which an initial disturbance sets off train of events that increases the disturbance even further. • Amplifies the deviation from the normal levels • Example: Oxytocin (suckling) • Important for amplification of level for action

33. Mechanisms of hormone actions • Hormone action mediated by the specific receptors • Most hormones circulate in blood, coming into contact withessentially all cells. However, a given hormone usually affectsonly a limited number of cells, which are called target cells. Atarget cell responds to a hormone because it bears receptors forthe hormone.

34. Hormone Receptors The receptor provides link between a specific extracellular hormoneand the activation of a specific signal-transduction system • Structure • Recognition domain binds hormone • Coupling domain generates signal • Location • cell membrane (e.g. for insulin) • cytoplasm (for steroids) • nucleus (e.g. for thyroid hormone) • Receptor capacity • exposure to excess hormone down-regulates capacity • low hormone concentration up-regulates capacity

35. Two general mechanisms ofhormone action • Second messengers – enzyme activity ↑↓(rapid, cytosolic effects) • Gene expression - enzymes synthesis ↑↓(slow, nuclear effects)

37. Mechanisms of Peptide Hormone Action • G proteins • are GTP-binding proteins • couple hormone receptors to adjacent effector molecule • have intrinsic GTPase activity • have three subunits: α, β, γ • α subunit bound to GDP → inactive G protein • α subunit bound to GTP → active G protein • the effect can be either stimulatory (Gs) or inhibitory (Gi) • Second messengers • cAMP second message system • IP3 mechanism • Ca2+-calmodulin mechanism

38. Signal transduction pathway involving adenylate cyclase

39. Cyclic AMP signaling-sequence of events • The hormone (1st messenger) binds to the membrane receptor; the membrane receptor changes shape and bind to G protein (GTP-binding protein) • G protein is activated; binds to GTP (Guanosine 5’- triphosphate) and release GDP • Activated G protein moves to membrane and binds and activates adenylate cyclase (GTP is hydrolysed by GTPase activity of G protein) • Activated adenylate cyclase converts ATP to cAMP (second messenger) (if inhibited, no catalysed reaction by AC) • cAMP is free to circulate inside the cell; triggers activation of one to several protein kinase molecules; protein kinase phosphorylates many proteins • The phosphorylated proteins may either be activated or inhibited by phosphorylation

40. Adenylyl cyclase forms cAMP, a “second messenger” that activates enzymes used in cellular responses. The phosphodiesterase enzymes “terminate” the second messenger cAMP.

41. Amplification effect Each protein kinase can catalyse hundreds of reactions The cAMP system rapidly amplifies the response capacity of cells: here, one “first messenger” led to the formation of one million product molecules.

42. PIP-calcium signaling mechanism This receptor-G-protein complex is linked to and activates phospholipase C, leading to an increase in IP3 and DAG, which work together to activate enzymes and to increase intracellular calcium levels.

43. PIP-calcium signaling mechanism • A hormone (first messenger) binding to its receptor causes the receptor to bind inactive G protein • G protein is activated; binds GTP & releases GDP • Activated G protein binds & activates a membrane-bound phospholipase enzyme; • G protein becomes inactive • Phospholipase splits phosphatidyl inositol biphosphate (PIP2) todiacylglycerol (DAG) & inositol triphosphate (IP3); • DAG activates protein kinases on the plasma membrane; IP3 triggers calcium ion release from the ER • Released calcium ions(second messengers) alter activity specific enzymes’ activity and ion channels or bind to the regulatory protein calmodulin; • Calmodulin also activates specific enzymes to amplify the cellular response

44. Ca-calmodulinsystem

45. Mechanisms of steroid Hormone Action • Modulation of gene expression • Steroid hormones bind to intracellular receptors • The steroid-receptor complex binds to DNA, turning specific genes on or off Steroid hormone receptor

46. Sequence of events for steroid hormone binding • Steroids are lipid-based and can diffuse into cells easily • No need for intracellular second messenger • Mobile receptors • Some steroids bind to a cytoplasmic receptor, which then translocates to the nucleus • Other receptors for steroids are located in the nucleus or are nuclear receptor proteins • In both cases, the steroid-receptor complex formed can then bind to specific regions of DNA and activate specific genes • Activated genes transcribe into messenger RNA and instruct the cell to synthesize specific enzyme proteins that change the metabolism of the target cell

50. Radioimmunoassay (RIA) (from the Nobel lecture by Dr. Rosalyn Yalow, 1977)