Hormone Action (Other than Insulin & Steroids)

1. Hormone Action(Other than Insulin & Steroids) Endocrinology Rounds July 29, 2009 Selina Liu PGY4 Endocrinology

2. Outline • Definitions • Hormone Classification & Structure • Hormone Synthesis & Release • Mechanisms of Action • Site of Action & Receptors • Endocrine Disorders & Pathophysiology

3. Definitions • endocrine– derived from Greek endo “within” krinein “to separate” • internal secretion of biologically active substances • act on target cells to cause effect Greenspan FS & Gardner DG (eds) Basic & Clinical Endocrinology 7th Edition 2004

4. Definitions • hormone – derived from: hormao - “I excite or arouse” Ernest Starling – 1905 Croonian Lectures of the Royal College of Physicians

5. Ernest Starling • April 17, 1866-May 2, 1927 • Professor of Physiology • University CollegeLondon • Also known for: • Starling’s Law • discovery of peristalsis • discovery of secretin (with William Bayliss) Henderson, J. J Endocrinol 2005;184: 5-10

6. Henderson, J. J Endocrinol 2005;184: 5-10 

7. Outline • Definitions • Hormone Classification & Structure • Hormone Synthesis & Release • Mechanisms of Action • Site of Action & Receptors • Endocrine Disorders & Pathophysiology

8. Classification • classified by structure • protein/peptide hormones • amino acid derivatives • tyrosine derivatives • tryptophan derivatives • lipid-derived hormones • cholesterol derivatives - steroid hormones • phospholipid derivatives - eicosanoids

9. Protein & Peptide Hormones • can be: • direct translation products of specific mRNAs • cleavage products of larger precursor proteins • modified peptides • variable size e.g. TRH – 3 amino acids hCG – 237 amino acids

10. Protein & Peptide Hormones TRH 3 amino acids hCG 237 amino acids

11. Protein & Peptide Hormones • often produced as large inactive precursors (“prohormone”) • require cleavage by proteases for activation i.e. endothelin-1 www.bioscience.org/2003/v8/e/1103/fig4.jpg

12. Protein & Peptide Hormones • other examples: • hypothalamic hormones • GHRH, GnRH, TRH, CRH, AVP, PRF, DA, somatostatin • pituitary hormones • GH, LH, FSH, TSH, ACTH, PRL, oxytocin • pancreatic hormones • insulin, glucagon, somatostatin, pancreatic polypeptide • calcium-regulating hormones • PTH, calcitonin

13. Protein & Peptide Hormones • other examples: • reproductive hormones • inhibin, oxytocin, hCG • plasma volume/sodium-regulating hormones • ANP, AVP, renin, angiotensin • CV hormones • endothelins, EPO, bradykinin • growth factors/cytokines • IGF, EGF, interleukins, TNF-a

14. http://www.rpi.edu/dept/bcbp/molbiochem/BiochSci/sbello/tyr_norep.gifhttp://www.rpi.edu/dept/bcbp/molbiochem/BiochSci/sbello/tyr_norep.gif http://www.colorado.edu/intphys/Class/IPHY3430-200/image/23-8.jpg Amino Acid Derivatives • Tyrosine Derivatives i.e. catecholamines dopamine thyroid hormones

15. Amino Acid Derivatives • Tryptophan Derivatives i.e. melatonin seratonin

16. Lipid-Derived Hormones • Steroid Hormones • derived from cholesterol (C27) • major groups: • progestins • glucocorticoids • mineralocorticoids • androgens • estrogens http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism_Fig2.html

17. Lipid-Derived Hormones • Eicosanoids • derived from phospholipids • i.e. arachidonic acid (C20 “eikos”) • major groups: • prostaglandins • thromboxanes • leukotrienes http://www.ufrgs.br/laprotox/eicosanoids-eng.htm

18. Outline • Definitions • Hormone Classification & Structure • Hormone Synthesis & Release • Mechanisms of Action • Site of Action & Receptors • Endocrine Disorders & Pathophysiology

19. Hormone Synthesis • Peptide Hormones (see next slides) • Amino Acid Derivatives • synthesized via side-chain modifications of tyrosine or tryptophan • Lipid Derivatives • steroids – (as per Rola’s talk last week) • eicosanoids – derived from arachidonic acid

20. Hormone Release • Vesicle-Mediated • peptide hormones • some nonpeptide hormones/neurotransmitters i.e. catecholamines, ACh, GABA • Non-Vesicle Mediated • steroids • eicosanoids

21. Peptide Hormone Synthesis & Release • occurs in cytoplasm • vesicle-mediated • via classical “secretory pathway” Nussey SS & Whitehead SA. Endocrinology An Integrated Approach 2001

22. Peptide Hormone Synthesis • Targeted to ER lumen via signal recognition particle • in Golgi apparatus, prohormone is cleaved into smaller peptides, stored in secretory granules Nussey SS & Whitehead SA. Endocrinology An Integrated Approach 2001

23. Peptide Hormone Release • stimulus for secretion may or may not be coupled with stimulus for synthesis • often synthesized and stored for later release • stimulus for secretion triggers fusion of secretory vesicle membrane with plasma membrane • release of vesicle contents by exocystosis Greenspan FS & Gardner DG (eds) Basic & Clinical Endocrinology 7th Edition 2004

24. Non-Vesicle Mediated Release • steroids – derived from cholesterol • synthesized in adrenals, gonads, placenta • also in nervous system, other tissues • eicosanoids – derived from arachidonic acid • not stored by cells • arachidonic acid precursor stores in membrane lipids • formation catalyzed by PLA2 or PLC • cleave esterified arachidonic acid from the 2 position of glycerophopholipids in the lipid bilayer of cell Greenspan FS & Gardner DG (eds) Basic & Clinical Endocrinology 7th Edition 2004

25. Steroid Hormone Synthesis http://www.gfmer.ch/Books/Reproductive_health/Steroid_hormone_metabolism_Fig2.html

26. Eicosanoid Synthesis http://www.ufrgs.br/laprotox/eicosanoids-eng.htm

27. Outline • Definitions • Hormone Classification & Structure • Hormone Synthesis & Release • Mechanisms of Action • Site of Action & Receptors • Endocrine Disorders & Pathophysiology

28. Hormone Actions • fetal development • cell growth & cancer • intermediary metabolism • CHO, fat, protein, amino acid, nucleic acid • mineral & water metabolism • cardiovascular/renal function • skeletal function • reproductive function • immune system • CNS • regulation of hormone production/release

29. Site of Actions • Endocrine effect – classical definition: • chemicals released by ductless gland • into circulation* • act on specific receptor on distant* target cell *ALSO : • paracrine/juxtacrine effects – on adjacent cells • autocrine effects – act on same cell • intracrine effects– within same cell • neuroendocrine effects

30. Nussey SS & Whitehead SA. Endocrinology An Integrated Approach 2001

31. Mechanism of Action • At Organ-System Level: • Free-standing endocrine glands • i.e. parathyroid gland • Hypothalamic-Pituitary-Target Gland systems • i.e. Hypothalamic-Pituitary-Thyroid axis

32. Hormone Free-Standing Gland Gland Target Cell EFFECT

33. PTH i.e. Parathyroid Gland Parathyroid Gland Target Cells i.e. bone, intestine, kidney Increase in serum calcium

34. Releasing Hormone - Trophic Hormone - Hormone EFFECT Hypothalamic-Pituitary-Target Axis Hypothalamus Pituitary Gland Target Cell

35. TRH - TSH - T4/T3 EFFECT Hypothalamic-Pituitary-Thyroid Axis Hypothalamus Pituitary Thyroid Target Cells

36. Mechanism of Action • At Molecular Level: • classified by receptor type at which they act • cell-surface receptors • intracellular receptors • cytoplasmic or nuclear

37. Cell-Surface Receptors • bind hydrophilic hormones • activate signal transduction cascade • involves generation of 2nd messengers or protein phosphorylation cascades

38. Mayo KE in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

39. Cell-Surface Receptors • very diverse group of receptors • common feature: • presence of > 1 hydrophobic membrane-spanning domains which anchor receptor at cell surface • extracellular regions – hormone binding • intracellular regions – direct enzymatic action or associate with intermediary proteins

40. Cell-Surface Receptors G-Protein Coupled Receptors Receptors with Protein Kinase Activity either intrinsic activity or recruit and activate protein kinases 3) Receptors with Guanylyl Cyclase Activity (intrinsic) 4) TNF Receptors 5) Transport Receptors Mayo KE in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

41. G-Protein Coupled Receptors • GPCRs – largest family of cell surface receptors • 7 transmembrane spanning domains • heptahelical or serpentine • coupled to G-protein • comprised of Ga subunit and bg subunit • on ligand-binding, exchange bound GDP for GTP on associated Ga subunits • i.e. b-adrenergic receptor

42. G-Protein Coupled Receptors http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.html

43. Receptors with Protein Kinase Activity • Receptor Tyrosine Kinases • cytoplasmic domains have intrinsic tyrosine kinase activity • i.e. insulin receptor, EGF-R, PDGF-R • TGFb Superfamily Receptors • cytoplasmic domains have intrinsic serine or threonine kinase activity • Cytokine Receptor Superfamily • recruit soluble protein tyrosine kinases of Janus kinase family (JAKs) • i.e. receptors for GH, PRL, interleukins

44. Receptor Tyrosine Kinases http://kph12.myweb.uga.edu/11_8tyrosinekinase.jpg

45. Receptors with Guanylyl Cyclase Activity • single chain transmembrane proteins • cytoplasmic domains with intrinsic guanylyl cyclase (GC) activity • promote production of cyclic GMP • related to, but distinct from, soluble GCs • 7 receptors: GC-A to GC-G • GC-A binds ANP, BNP

46. TNF Receptors • large and diverse family of receptors (~30) • mediate action of TNF • homologous extracellular domains • classified into 2 groups based on intracellular domain • those containing deathdomain • those lacking death domain • both groups mediate signalling leading to apoptosis

47. Transport Receptors • serve to transport substances from plasma to cell • as opposed to activating classic signalling pathways • bind ligand, cluster into coated pits and are endocytosed into vesicles • ligand dissociated & utilized, receptor either degraded or recycled • i.e. LDL receptor, transferrin receptor

48. Intracellular Receptors • bind hydrophobic hormones that enter cell directly by diffusion across lipid bilayer • cytoplasmic or nuclear receptors • are ligand-activated transcription factors • directly mediate gene transcription

49. Mayo KE in Melmed S & Conn PM (eds) Endocrinology: Basic & Clinical Principles 2nd Edition 2005

50. Intracellular Receptors • main group - nuclear receptor superfamily • receptors for: • steroids, thyroid hormone, vitamin D, PPAR • large number of orphan receptors • mediate genomic and nongenomic effects