Categories of Chemical Regulators

1. Categories of Chemical Regulators Intracrine Endocrine Autocrine Ectocrine Paracrine

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

3. Endocrinology: study of hormones Transport Gland Hormones Target Cell 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 lordosis Mounting behavior

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. Hormones: structural classification • 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?.....

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

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

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

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. OH H O CH3 H N H C H OH C H epinephrine 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

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

17. OH COOH PGF2alpha OH OH 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) PROSTAGLANDIN

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

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

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

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 Transport Gland Hormone Target Cell

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

24. Corticosteroid Binding Globulin CRH ACTH STRESSOR Central Nervous System hypothalamus pituitary adrenals Glucocorticoids (cortisol, corticosterone) 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. total CORT 60 50 40 Total CORT (ng/ml) 30 20 1 brood 10 0 0-3 minutes 30 minutes 600 CBG capacity 500 400 Specific Binding (nM) 300 200 100 2-3 broods 0 pugetensis oriantha gambelii 3.5 Free CORT 3 2.5 2 Free CORT (ng/ml) 1.5 1 1-2 broods .5 0 0-3 minutes 30 minutes White-crowned sparrows

28. Transport: Binding Proteins BINDING PROTEIN ABBREVIATION HORMONES BOUND Corticosteroid-binding globulin CBG glucocorticoids and progesterone Sex-steroid binding globulin SBG or SSBG Testosterone and estradiol Progesterone-binding globulin PBG progesterone Thyroxine-binding protein TBP Thyroxine and tri- iodothyronine Growth Hormone binding protein GH-BP Growth hormone Insulin-like growth factor binding IGF-BPs Insulin-like growth proteins factors I and II Neurophysins I and II - Vasopressin and oxytocin Corticotropin releasing CRF-BP Corticotropin 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 Hormone Target Cell

31. Endocrine Glands

32. The human brain

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

34. Human Brain: Sagittal Section

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

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

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

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

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

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

41. Hypothalamus-pituitary control center hypothalamus Anterior pituitary

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

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

44. Endocrinology: study of hormones Transport Gland Hormone Target Cell 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. G-protein coupled receptor Receptor as Enzyme Ligand-gated ion channel G ↑↓ second messengers Intracellular Receptor ↑↓ second messengers effector recognition site + + + + cell membrane nucleus

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

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

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 (Gs) or inhibitory (Gi) • Once GTP returns to the inactive form (GDP), the -subunit is no longer active, and returns to the -subunit.

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