1. Categories of Chemical Regulators Intracrine Autocrine Paracrine Endocrine Ectocrine

2. Endocrinology: study of hormones Gland Transport Target Cell Hormone General Features of the endocrine system: ductless rich blood supply secreted into the blood can reach virtually every cell in the body hormone receptors are very specific

3. Endocrinology: study of hormones Gland Transport Target Cell Hormones Functional classification Structural classification

4. Hormones: functional classification Metabolism (i.e.: nutrient breakdown and absorbtion, and anabolic and catabolic metabolism) Reproductive function Growth and metamorphosis Osmoregulation and excretion of water and salts Synthesis and release of other hormones Permissive actions Stimulate muscle contraction (especially smooth muscle in the gut and genital tract) Activational and/or Organizational effects on behavior

5. Organizational vs. Activational Example: Sexual behavior Mounting behavior lordosis

6. Hormones: functional classification Metabolism (i.e.: nutrient breakdown and absorbtion, and anabolic and catabolic metabolism) Reproductive function Growth and metamorphosis Osmoregulation and excretion of water and salts Synthesis and release of other hormones Permissive actions Stimulate muscle contraction (especially smooth muscle in the gut and genital tract) Activational and/or Organizational effects on behavior Facultative Actions

7. Ham Creek, Hudson Valley

8. Helps us understand how hormones are: –Synthesized –Secreted –Transported –Have effects at the Target Cell To start: what are the 4 major groups of organic compounds? Biochem majors?..... Hormones: structural classification

9. Peptide Hormones –Made up of amino acid building blocks 3 to <180 amino acids in length –Soluble in water? Yes –Synthesis Hormones: structural classification pGLU – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 GnRH

10. Synthesis and secretion of a peptide hormone NUCLEUS DNA MEMBRANE CELL TRANSCRIPTION RNA PROCESSING RNA TRANSPORT mRNA TRANSLATION PROTEIN SYNTHESIS mRNA PROTEIN PROCESSING SECRETION BY EXOCYTOSIS PACKAGED IN A SECRETORY VESICLE Peptide hormone secretion can be: 1) constitutive 2) regulated releasing hormone

11. Hormones: structural classification STEROIDS –All steroids are made from cholesterol –Water soluble? NO Almost all have binding proteins for transport in blood They can pass across membranes –No storage –Receptors are intracellular –Synthesis

12. Synthesis and secretion of a Steroid hormone NUCLEUS MEMBRANE CELL SECRETION Steroid hormone secretion must be: constitutive It cannot be regulated HO C-CH 2 -C 5 H 11 CH 3 Cholesterol stimulating hormone Cholesterol store in cell Mitochondria It also may occur in the endoplasmic reticulum enzymes Protein synthesis for: -Cell growth -cell division -Enzymes for mitochondria steroid

13. Steroid Biosynthesis All steroids start from cholesterol Each arrow is one enzymatic step Synthesis of a certain steroid will only occur if the appropriate enzymes are present

14. Hormones: structural classification Monoamines –Epinephrine, norepinephrine and dopamine All derived from a single amino acid: tyrosine –Melatonin and serotonin Derived from the amino acid tryptophan –Synthesis: Enzymes present in cell alter the amino acid epinephrine OH CHCH HOHO HCHHCH HNHN CH3

15. Hormones: structural classification Thyroid hormones –Modified from amino acid tyrosine Iodine is incorporated (think salt) –Two forms: thyroxine (T4 = four iodines) and tri-iodothyronine (T3 = three iodines) –Soluble in water? No –Synthesis

16. Synthesis of thyroid hormones Cell membrane cytoplasm Golgi apparatus CH2 OH CH2 OH vessicle thyroglobulin I I I I CH2 OH I I CH2 OH I I enzymes lysozyme OH I I CH2 O I I OH I I CH2 O I I OH I I CH2 O I I I I I I stimulating hormone

17. Hormones: structural classification EICOSANOIDS –Lipid hormones –All are derived from arachidonic acid (a fatty acid) Prostaglandins-stimulate smooth muscle, induce inflammation and fever –Aspirin inhibits prostaglandin synthesis Leukotrienes-contribute to inflammatory and allergic responses Thromboxanes-facilitates clotting of blood platelets –Synthesis Arachidonic acid is synthesized from diacyl glycerol (DAG) COOH OH PGF2alpha PROSTAGLANDIN

18. Regulation of Hormone Levels How does the body recognize and regulate how much hormone is present in the blood?

19. Negative Feedback simple HYPOTHALAMUS PITUITARY ADRENALS Glucocorticoids (i.e. cortisol) CRH ACTH --- = negative feedback

20. Negative Feedback HYPOTHALAMUS PITUITARY TESTIS Testosterone --- = negative feedback GnRH - - LH

21. Negative Feedback A process where increasing hormone levels serve to shut down releasing and stimulating hormones ‘upstream’ set-point level can be changed depending on season, parental care, environmental conditions, etc. Positive Feedback A process where increasing hormone levels stimulate further secretion of releasing and stimulating hormones

22. Endocrinology: study of hormones Gland Transport Target Cell Hormone

23. Binding Proteins 3 Important concepts Binding globulin characteristics capacity and affinity two examples Other binding proteins

24. Corticosteroid Binding Globulin hypothalamus STRESSOR Central Nervous System pituitary adrenals Glucocorticoids (cortisol, corticosterone) CRH ACTH Target Tissue

25. Transport Binding proteins: –carry hormones in the blood Important concepts –Bound vs. Free: In the blood there is hormone bound to binding globulin, and hormone that is free –Only free hormone can exit the blood stream only free reaches tissue to bind receptors only free can be broken down in the liver –↑ binding protein = ↑ hormone bound, ? free hormone ↑ binding protein = ↑ hormone bound, ↓ free hormone So, binding proteins can regulate –Bioavailability –Clearance rates

26. Characteristics of Binding Proteins Affinity –how well hormone binds to binding globulin tightly bound = high affinity loosely bound = low affinity –Increase affinity…what happens to free hormone? –Human Example Capacity –total number of binding globulins present –Decrease capacity…what happens to free hormone? –Bird Example

27. 1 brood 1-2 broods 2-3 broods 0 10 20 30 40 50 60 Total CORT (ng/ml) 0-3 minutes30 minutes total CORT 0 100 200 300 400 500 600 Specific Binding (nM) pugetensisoriantha gambelii CBG capacity 0.5 1 1.5 2 2.5 3 3.5 Free CORT (ng/ml) 0-3 minutes 30 minutes Free CORT White-crowned sparrows

28. Transport: Binding Proteins Corticosteroid-binding globulin CBGglucocorticoids and progesterone Sex-steroid binding globulinSBG or SSBGTestosterone and estradiol Progesterone-binding globulinPBGprogesterone BINDING PROTEINABBREVIATIONHORMONES BOUND Thyroxine-binding proteinTBPThyroxine and tri- iodothyronine Growth Hormone binding proteinGH-BPGrowth hormone Insulin-like growth factor binding IGF-BPsInsulin-like growth proteins factors I and II Neurophysins I and II-Vasopressin and oxytocin Corticotropin releasing CRF-BPCorticotropin releasing factor-binding protein factor

29. Review Binding proteins: carry hormones in the blood Important concepts - Bound vs. Free: In the blood there is hormone bound to binding globulin, and hormone that is free - Binding proteins regulate how much free H is available to tissues or alter clearance rate (how much will be broken down) Affinity vs. capacity -CBG mutations in humans -CBG altering free CORT levels: bird example So, binding proteins can regulate bioavailability and clearance rate of hormones

30. Endocrinology: study of hormones Glands Transport Target Cell Hormone

31. Endocrine Glands

32. The human brain

33. Human Brain: coronal section Lateral ventricles 3 rd ventricle thalamus hypothalamus

34. Human Brain: Sagittal Section

35. Anterior Pituitary (adenohypophysis) (pars distalis) Posterior Pituitary (neurohypophysis) (pars nervosa) Intermediate lobe (pars intermedia) Hypothalamus THE NOSE Infundibulum Mammalian Pituitary OC

36. Posterior Pituitary (neurohypophysis) (pars nervosa) Hypothalamus THE NOSE Infundibulum Oxytocin Vasopressin OC

37. Median Eminence Anterior Pituitary (adenohypophysis) (pars distalis) Posterior Pituitary (neurohypophysis) (pars nervosa) Intermediate lobe (pars intermedia) Hypothalamus THE NOSE OC Releasing and Inhibiting hormones are secreted from the hypothalamus

38. Portal System Anterior Pituitary (pars distalis) Posterior Pituitary (pars nervosa) Intermediate lobe (pars intermedia) Median Eminence Hypothalamus the nose

39. Hypothalamo-pituitary blood portal system Median eminence Pars distalis Hypothalamo- portal vessels Pars nervosa Median eminence Pars distalis Hypothalamo- portal vessels

40. Median Eminence Anterior Pituitary (adenohypophysis) (pars distalis) Posterior Pituitary (neurohypophysis) (pars nervosa) Intermediate lobe (pars intermedia) Hypothalamus THE NOSE OC ACTH TSH PRL LH FSH GH  endorphins MSH Releasing and Inhibiting hormones are secreted from the hypothalamus

41. Hypothalamus-pituitary control center hypothalamus Anterior pituitary

42. Hypothalamus Posterior pituitary or Pars nervosa Median eminence Anterior pituitary Portal system

43. Mammal hypothalamo-pituitary unit Hypothalamus Pars nervosa Median eminence Hypothalamo- Portal vessels Pars distalis Pars intermedia

44. Endocrinology: study of hormones Gland Transport Target Cell Hormone Mechanism of Action

45. Characteristics of Receptors Two major components –Recognition site: specific for hormone –Effector: the portion of the receptor that changes upon hormone binding and initiates action in the cell

46. Receptor as Enzyme Ligand-gated ion channel G G-protein coupled receptor + + ++ ↑↓ second messengers nucleus Intracellular Receptor cell membrane

47. Receptor as Enzyme G Ligand-gated ion channel G-protein coupled receptor ↑↓ second messengers nucleus + + + Intracellular Receptor

48. Receptor as Enzyme G Ligand-gated ion channel G-protein coupled receptor ↑↓ second messengers nucleus mRNA + + + Intracellular Receptor

49. G-protein-coupled Receptors G proteins activate enzymes –Adenylate cyclase which produces cAMP –Phospholipase C which produces IP3 and DAG G proteins can be stimulatory (G s ) or inhibitory (G i ) Once GTP returns to the inactive form (GDP), the  -subunit is no longer active, and returns to the  -subunit.

50. Steroid Receptors Capillary space Extra- cellular space Intra-cellular space CytoplasmNucleus 90 r r r r DNA 90 r hormone Heat shock protein 90 Hormone receptor r Hormone-receptor binds to DNA RNA processing mRNA Ribosomes Protein synthesis r r 90 r

51. Steroid Receptors are transcription factors They usually dimerize Two major components: –Ligand binding domain (recognition site) –DNA binding domain (effector) Contains Zinc fingers Binds to DNA at Hormone Response Element R R Ligand binding domain Zinc fingers at the DNA binding domain DNA Hormone Response Element (HRE)

52. Characteristics of Receptors Two major components –Recognition site: specific for hormone –Effector: the portion of the receptor that changes upon hormone binding and initiates action in the cell Common properties of all receptors –Specificity –Capacity –Affinity H + R  HR(law of mass action)

54. 100% receptors bound GR GR Kd = 4.0 nM (nM)

55. 100% receptors bound MR Equilibrium Saturation Binding Curve 0.02.55.07.510.012.515.017.520.022.525.0 0 10 20 30 40 50 60 70 80 MR [radioactive CORT in experiment] [radioactive CORT bound] MR Kd = 0.2 nM (nM)

56. GR MR MR Kd = 0.2 nM GR Kd = 4.0 nM (nM)