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  • 1. INTRODUCTION • Endocrine(Gk- I separate within) • Chemical messenger systemi. Neurotransmitters ii. Endocrine hormones iii. Neuroendocrine hormones iv. Paracrines v. Autocrines vi. Cytokines
  • 2. HISTORY • Arnold A Berthold (1849)- effect of testosterone on rooster. • Claude Bernard (1854)- internal mileu • Ernest Henry Starling (1902)- with Bayliss demonstrated that secretin stimulates pancreatic secretion. He was the first to use the term hormone (to excite) • SIR THOMAS BEATSON- progress of BREAST cancer can be delayed by removing ovaries (estrogen) • EARL WILBUR SUTHERLAND Jr.(1971)- discovery of second messenger • BERSON AND YALOW(1960s)- radioimmunoassay • DALY et al.(1974)- Cytochemical assays
  • 4. HORMONES • Gk :Horman= to set in motion • DEFINITION • CHARECTERESTICi. Distant target cell ii. Receptor iii. Regulates existing fundamental bodily process but do not initiate cellular reaction. iv. Secreted in extremely low concentration v. Long latent period than neurons. vi. Metabolized rapidly in kidney and liver
  • 5. •CHEMISTRY1) Peptide Hormone 2 Enzymes in the 1 Messenger RNA on the ER chop off the signal sequence, creating an inactive prohormone. ribosome binds amino acids into a peptide chain called a preprohormone. The chain is directed into the ER lumen by a signal sequence of amino acids. 3 The prohormone passes from the ER through the Golgi complex. 4 Secretory vesicles containing enzymes and prohormone bud off the Golgi. The enzymes chop the prohormone into one or more active peptides plus additional peptide fragments. 5 The secretory vesicle releases its contents by exocytosis into the extracellular space. 6 The hormone moves into the circulation for transport to its target. Golgi complex Endoplasmic reticulum (ER) To target Ribosome Transport vesicle 3 Active hormone Peptide fragment 4 6 Secretory vesicle Prohormone 5 Release signal Capillary endothelium 2 1 mRNA Signal sequence Preprohormone Cytoplasm ECF Plasma Figure 7-3
  • 6. 2) Steroid Hormones Steroid hormones are derived from cholesterol Figure 7-6
  • 7. 3)Amine Hormones: Structure Tyrosine-derived amine hormones Figure 7-8
  • 8. Hormone Transport Unbound to plasma protein Water soluble hormones Catecholamines,peptides &protein hormones. Bound to plasma protein Lipid soluble hormones  Steroid –SBP  Testosterone and estrogen- SHBG  Progesterone, cortisol and other corticosteroidTRANSCORTIN Free hormone is the active hormone.
  • 9. Plasma Concentration Hormones are secreted in very low concentration in pulsatile manner. RYTHMS:1. CIRCADIAN(Diurnal) 2. ULTRADIAN
  • 10. Half- Life of some Hormones Class of Hormone Hormone Half- Life Protein & Peptide Hormones •ADH •Oxytocin •Insulin •Prolactin •Growth Hormone <1 min <1 Min 5 min 12 sec <30 min Amines •Epinephrine •Thyroxin 10 sec 5-7 days Steroid Hormones •Aldosterone •Cortisol 30 Min 90-100 Min
  • 11. Hormone Disposal 1. Target cell uptake & Intracellular degradation. 2. Metabolic degradation by Liver & Kidney 3. Urinary & Biliary Disposal Metabolic clearance rate (MCR) • Defines the quantitative removal of hormone from plasma • The bulk of hormone is cleared by liver and kidneys • Only a small fraction is removed by target tissue – protein and amine hormones bind to receptors and are internalized and degraded – Steroid and thyroid hormones are degraded after hormonereceptor complex binds to nuclear chromatin MCR = Rate of disappearance of hormone from plasma / ( ml cleared/ minute ) Concentration of hormone
  • 12. Receptors Characteristic Of Hormone Receptors Specificity Location 1. Internal 2. External Affinity Density Regulation 1.Up 2. Down Spare Receptor
  • 13. Spare receptors • In most systems the maximum biological response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell. • Examples: – insulin stimulates maximum glucose oxidation in adipocytes with only 2-3% of receptors bound – LH stimulates maximum testosterone production in Leydig cells when only 1% of receptors are bound • Maximum response with 2-3% receptor occupancy. 97% of receptors are “spare
  • 14. Classification of Membrane Receptor
  • 15. Protein tyrosine kinase receptors
  • 16. Second messengers for cell-surface receptors  Second messenger systems include:  Adenylate cyclase which catalyzes the conversion of ATP to cyclic AMP,  Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides)  Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.
  • 17. Functions of Hormones 1. Help regulate:  Chemical composition & volume of internal environment.  Metabolism & Energy balance.  Contraction of smooth muscle & cardiac muscle fiber.  Glandular secretion.  Immune system activities.
  • 18. 2. Control Growth & Development 3.Regulate operation of reproductive system. 4.Help establish circadian rhythms.
  • 19. REGULATION OF HORMONES • • • • Direct control (substances) Nervous control (neurosecretion) Feedback control (Hormone concentration) Chronotropic control
  • 20. Neural Control • Release of Oxytocin, which fills the milk ducts in response to the stimulus of suckling. • Release of Aldosterone, which augments the circulatory volume in response to upright posture. • Release of Melatonin in response to darkness.
  • 21. Feedback Loops Figure 6-26: Negative and positive feedback
  • 22. Negative Feedback Controls Ultra short loop fb Figure 7-14
  • 23. Chronotropic Control • • • • • • Pulsatile release of hormone. Diurnal variation. Sleep Wake Cycle variation. Menstrual Rhythm. Seasonal Rhythm Developmental Rhythm.
  • 24. MECHANISM Hormone+ Receptor Conformational change in the receptor (SIGNAL) Transduced Activation of one or more intracellular messenger (TRANSDUCTION) Messenger molecule bind to effector proteins Regulate/ modify specific cellular function (CELLULAR RESPONSE) SIGNAL TRANSDUCTION PATHWAY/ SIGNALLING PATHWAY
  • 25. VARIOUS MODES OF INFORMATIONAL CONDUCTION AND TRANSFER BY SIGNALLING PATHWAY – 1. Covalent phosphorylation of proteins and lipids 2. Non-covalent GTP binding to G-proteins 3. Non-covalent binding of cyclic nucleotide monophosphate 4. Non-covalent Ca++ binding and activation of proteins 5. Generation of lipid information molecules 1.
  • 26. 2- GPCR+ GDP- INACTIVE, GPCR+ ATP- ACTIVE GEFs G-protein GTP GDP Inactivation of G-protein by- i) Intrinsic GTPase activity ii) Regulator of G protein signalling (RGS) 3- 4GTP NO GUANYLYL CYCLASE cGMP PKG cGMP [Ca++]ICF PHOPHODIESTERASE SILDENAFIL (VIAGRA) GMP
  • 28. • Signaling from membrane receptors 1-RECEPTORS USING G PROTEIN Modulation of levels of intracellular messenger -cAMP -DAG -IP3 Cellular response
  • 29. 2-RECEPTOR TYROSINE KINASE • Gp 1-Growth factors (PDGF, EGF) • Gp 2-Insulin & IGF GF (ERKs)
  • 30. 3-ENZYME LINKED RECEPTORS ASSOCIATED WITH CYTOPLASMIC TYROSINE KINASE EXAMPLE• Growth hormone • Prolactin • Erythropoietinleptin • Leptin JAK-Janus Kinase 2 STAT-Signal Transducer and Activator of Transcription SOCS-Suppressors Of Cytokine Signaling
  • 31. 4-RECEPTOR SERINE/THREONINE KINASE TGF β related hormones • Anti-mullerian hormone • Inhibin
  • 32. 5-Receptors regulating ion channel • Calcium channel
  • 33. Signaling from intracellular receptor• • • • Steroid hormone Thyroid hormone 1,25-DHCC Vit-A,D,E,K, Retinoic acid Nuclear receptor superfamily- 3 domainsi) Aminoterminus domain- hormone independent transcription ii) DNA binding domain- 2 Zn finger motif Zn finger motif+ Neighboring A.A.= HRE (recognize and bind specific DNA sequence) iii) Carboxyl termina domain-subdomainsa)a site of hormone recognition & binding b)a hormone dependent transcriptional activation domain c)a nuclear translocation signal d)a binding domain for HSP (Chaperone) e)a dimerization subdomain.
  • 34. Pathway-1 Cytoplasmic/nuclear receptor
  • 35. Pathway 2• Only nuclear receptor • TR, RXR, Vit-D HDAC
  • 36. Hormone assay • Radioimmunoassay • ELISA
  • 37. Hormone deficiency •Congenital- CAH •Autoimmune- Type l DM •Iatrogenic Hormone excess •Tumor - Gigantism •Autoimmune- Grave’s Ds APPLIED Hormone resistance •Receptor defect- Type ll DM Second messenger defect •Atopic dermatitis