Transcript LowSlides
ENDOCRINE SYSTEM: FALL2003 MARTIN G. LOW, DEPT. PHYSIOLOGY Q: WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM? Q: WHY DO VERTEBRATES HAVE AN ENDOCRINE SYSTEM? A: ALTHOUGH IT ALLOWS EXTREMELY RAPID COMMUNICATION THE “HARD WIRING” OF THE NERVOUS SYSTEM IS TOO “EXPENSIVE”, INEFFICIENT (AND UNNECCESARY) FOR THE DELIVERY OF MOLECULAR SIGNALS TO EVERY CELL IN THE BODY. THE CARDIOVASCULAR SYSTEM, WHICH IS MOSTLY DEVOTED TO TRANSPORTING OXYGEN AND NUTRIENTS, CAN ALSO PROVIDE A HIGHLY EFFICIENT, BUT RELATIVELY SLOW SYSTEM FOR DELIVERING “SOLUBLE” MESSENGER MOLECULES TO ESSENTIALLY EVERY CELL IN THE BODY. HOWEVER TO ENSURE FIDELITY AND SPECIFICITY OF THE SIGNALLING PROCESS THESE “SOLUBLE MESSENGERS” MUST BE GUIDED TO THE CORRECT DESTINATION BY A “MOLECULAR ADDRESS” 1 ENDOCRINE STIMULUS CELL A TRANSPORT VIA BLOODSTREAM TO DISTANT PARTS OF THE BODY CELL B HORMONE SECRETION 2 RESPONSE NEUROCRINE CELL A NEURON CELL B TRANSPORT VIA BLOODSTREAM TO DISTANT TARGET TISSUES HORMONE HORMONE 3 CELL TYPE A PARACRINE SIGNALLING BETWEEN “NEIGHBORING” BUT DIFFERENT CELLS VIA ECF 4 CELL TYPE B CELL TYPE X AUTOCRINE CELL TYPE X CELL TYPE X SIGNALLING BETWEEN “NEIGHBORING” IDENTICAL CELLS OF SAME TYPE SUMMARY OF THE MAJOR COMPONENTS OF THE ENDOCRINE SYSTEM BRAIN ANTERIOR LOBE OF PITUITARY GnRH PRL BREAST GHRH LH/FSH GH LIVER GONADS IGF-1 MILK VASOPRESSIN POSTERIOR LOBE OF PITUITARY TRH DIET CRH TSH ACTH GLUCOSE THYROID ADRENAL CORTEX PANCREAS T3 +T4 TARGET TISSUES CALCIUM PARATHYROID PTH STEROIDS STEROIDS ADRENAL CORTEX OXYTOCIN GLUCAGON INSULIN FEEDBACK LOOPS BRAIN RH = RELEASING HORMONE HYPOTHALAMUS IH ULTRA SHORT L0OP SHORT LOOP RH IH = INHIBITORY HORMONE LONG LOOP PITUITARY LONG LOOP TROPIC HORMONE PERIPHERAL ENDOCRINE GLAND HORMONE TARGET TISSUES THREE DIFFERENT SECRETION MECHANISMS *PEPTIDE *STEROID *THYROID FEEDBACK REGULATION OF PITUITARY HORMONE SECRETION STRUCTURE & FUNCTION OF MAJOR HORMONES CHEMICAL STRUCTURE HORMONE M.W. TRIIODOTHYRONINE (T3) <1000 THYROXINE (T4) <1000 STEROIDS <1000 ARG-VASOPRESSIN (ADH) ~1000 OXYTOCIN ~1000 GLUCAGON ~3,500 29-RESIDUE PEPTIDE CALCITONIN ~ 4,000 32-RESIDUE PEPTIDE ADRENOCORICOTROPHIC HORMONE (ACTH) 4,500 INSULIN 6,000 PARATHYROID HORMONE 9,500 PROLACTIN (PRL) 23,000 GROWTH HORMONE (GH) 22,000 THYROID-STIMULATING HORMONE (TSH) 28,000 IODINATED TYROSINE DERIVATIVES CHOLESTEROL DERIVATIVES CHORIONIC GONADOTROPHIN (hCG) GROWTH, METABOLISM & DEVELOPMENT '' ANTI-DIURETIC HORMONE (S-S) LINKED CYCLIC NONAPEPTIDES 39-RESIDUE PEPTIDE DERIVED FROM 31K POMC PRECURSOR 51-RESIDUE PEPTIDE WITH (S-S)-LINKED A AND B CHAINS 84-RESIDUE PEPTIDE 198 /191 RESIDUE GLYCOPROTEINS WITH ~ 80% HOMOLOGY GLYCOPROTEINS WITH: LUTEINZING HORMONE (LH) 30,000 FOLLICLE-STIMULATING HORMONE (FSH) MAJOR FUNCTION SUCKLING RESPONSE PLASMA GLUCOSE PLASMA Ca STIMULATES RELEASE OF CORTICAL STEROIDS PLASMA GLUCOSE LIPOLYSIS PLASMA CALCIUM LACTOGENESIS GROWTH / METABOLISM STIMULATES RELEASE OF T3 AND T4 COMMON ALPHA SUBUNIT REGULATION OF 30,000 AND VARIABLE BETA SUBUNIT SPERMATOGENESIS AND OOGENESIS 57,000 LEPTIN: 16kDa 139-RESIDUE PEPTIDE MAINTENANCE OF CORPUS LUTEUM CELL SURFACE RECEPTORS AND THEIR TRANSDUCERS: GROUP I RECEPTOR / HORMONE β1, β2, β3 - ADRENERGIC MAJOR TRANSDUCERS G PROTEIN : CYCLASE α1- ADRENERGIC G PROTEIN : PLC-β α2- ADRENERGIC G PROTEIN : PLC-β AND CYCLASE M1- MUSCARINIC G PROTEIN : PLC-β D2-DOPAMINERGIC G PROTEIN : PLC-β AND CYCLASE HISTAMINE G PROTEIN : PLC-β BRADYKININ G PROTEIN : PLC-β ANGIOTENSIN G PROTEIN : PLC-β VASOPRESSIN G PROTEIN : PLC-β GLUCAGON G PROTEIN : AND CYCLASE CALCITONIN G PROTEIN : AND CYCLASE PARATHYROID HORMONE G PROTEIN : AND CYCLASE PROSTAGLANDIN E2 G PROTEIN : AND CYCLASE LEUKOTRIENES G PROTEIN : PLC-β CELL SURFACE RECEPTORS TRANSDUCERS AND MESSENGERS?: GROUP II RECEPTOR / HORMONE MAJOR TRANSDUCERS THROMBOXANE A2 G PROTEIN : PLC-β THYROTROPIN-RELEASING HORMONE (TRH) G PROTEIN : PLC-β THYROID-STIMULATING HORMONE (TSH) G PROTEIN : CYCLASE FOLLICLE-STIMULATING HORMONE (FSH) G PROTEIN : CYCLASE LUTEINIZING HORMONE (LH) G PROTEIN : CYCLASE EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR TYROSINE KINASE: PLC-γ PLATELET-DERIVED GROWTH FACTOR (PDGF) RECEPTOR TYROSINE KINASE; PLC-γ INSULIN RECEPTOR TYROSINE KINASE; IRS-1 INSULIN -LIKE GROWTH FACTOR 1 ( IGF-1) RECEPTOR TYROSINE KINASE; IRS-1 GROWTH HORMONE (GH) NON-RECEPTOR TYROSINE KINASE; JAK/Stat PROLACTIN (PRL) NON-RECEPTOR TYROSINE KINASE; JAK/Stat ACTIVIN/INHIBIN (TGF-β FAMILY) RECEPTOR Ser/Thr KINASE:Smad NEUROHYPOPHYSIS (POSTERIOR PITUITARY) ADENOHYPOPHYSIS (ANTERIOR PITUITARY) HYPOTHALAMUS NEUROCRINE CELLS RELEASING AND INHIBITING HORMONES MEDIAN EMINENCE AND NEURAL STALK ADH OXYTOCIN LONG PORTAL VEIN 2 1 SUPERIOR HYPOPHYSEAL ARTERY 4 3 ENDOCRINE CELLS INFERIOR HYPOPHYSEAL ARTERY ANTERIOR PITUITARY HORMONES ACTH GH EFFERENT VEINS PRL LH TSH FSH/LH GH CONCENTRATION CONTROL AFTER 2 DAY FAST GH SECRETION IS TIGHTLY COUPLED TO SLEEP PERIOD FASTING INCREASES GH SECRETION AND UNCOUPLES IT FROM SLEEP PERIOD MAGNITUDE GREATER DURING PUBERTY 2pm 8pm 2am 8am 8am 2pm 8pm 2am 8am 8am 2pm 8pm 2am 8am 8am 2pm 8pm 2am 8am GH SECRETORY RATE 8am PREPROOPIOMELANOCORTIN 26 265 + 146 76 + + ACTH + -LIPOTROPIN (91) -LIPOTROPIN (58) -ENDORPHIN (31) STRUCTURAL ORGANIZATION OF MAMMALIAN PREPROGLUCAGON 31 1 GRPP 69 64 GLUCAGON IP-1 107/8 GLP-1 GLP-2 IP-2 MPGF GLICENTIN OXYNTOMODULIN 158 126 GLUCAGON MPGF GLP-2 (1-33) - GLP-2 (3-33) - bioactive bioinactive GLICENTIN PANCREAS GLUCAGON MPGF INTESTINE* GLP-1 BRAIN “ENTEROGLUCAGONS” OXYNTOMODULIN-1 GLP-2 * IP-2 HORMONES HAVE VARIABLE IN VIVO “STABILITY” t½ HORMONE FSH 3h CORTISOL 70 min ALDOSTERONE 70 min LH 60 min ACTH I5 min ADH 8 min INSULIN 5-8 min OXYTOCIN 3-5 min POTENTIAL REASONS FOR VARIABLE STABILITY STEROIDS ARE HYDROPHOBIC AND MAY PARTITION INTO MEMBRANES AND ADIPOSE TISSUE HORMONE CLEAVED BY SPECIFIC PEPTIDASES IN PLASMA HORMONE FORMS COMPLEX WITH BINDING PROTEIN WHICH PROTECTS IT FROM DEGRADATION SHORT PEPTIDES ARE PARTICULARLY VULNERABLE TO DEGRADATION BECAUSE THERE ARE FEW CONSTRAINTS ON THEIR CONFORMATION PERIPHERAL CONCENTRATION (ng/ml) GnRH PULSE FREQUENCY REGULATES SECRETION OF LH AND FSH LH LH PLASMA LH FSH 0 FSH 10 20 30 40 DAYS HOURS INTRACELLULAR RECEPTORS:“LIGAND-ACTIVATED TRANSCRIPTION FACTORS” HORMONES WITH INTRACELLULAR RECEPTORS ARE HYDROPHOBIC ALLOWING DIFFUSION ACROSS PLASMA MEMBRANE HIGHLY VARIABLE TRANSCRIPTION-ACTIVATION DOMAIN HIGHLY CONSERVED (66 AMINO ACID) DNA-BINDING DOMAIN CONTAINING TWO “ZINC FINGERS” N “CONSERVED” 240 AMINO ACID HORMONE-BINDING DOMAIN (STEROIDS ONLY) C CELL SURFACE RECEPTORS REQUIRE TRANSMEMBRANE SIGNALLING POLYPEPTIDE HORMONES ARE HYDROPHILIC AND CANNOT DIFFUSE ACROSS THE PLASMA MEMBRANE THIS PROBLEM IS SOLVED BY UTILISING THE ENERGY OF HORMONE BINDING AT THE CELL SURFACE TO ALTER CONFORMATION OF TRANSMEMBRANE PROTEINS AND THEIR INTERACTIONS WITH INTRACELLULAR PROTEINS OTHER STEROID HORMONES GLUCOCORTICOIDS (GR) PROGESTERONE (PR) TESTOSTERONE (AR) ESTROGEN (ER) 1 STEROID HORMONES DIFFUSE ACROSS PLASMA MEMBRANE STEROID HORMONES BIND TO SPECIFIC, SOLUBLE INTRACELLULAR RECEPTORS 2 GLUCOCORTICOSTEROID HORMONES BIND TO A SOLUBLE INTRACELLULAR GR RECEPTOR: hsp90 COMPLEX release of inhibitory hsp90 proteins reveals nuclear localization signal on GR receptor NUCLEUS + 3 GRE: GLUCOCORTICOID RESPONSE ELEMENT HRE: HORMONE RESPONSE ELEMENT +ve HRE - ve HRE STEROID-RESPONSIVE TARGET GENES STEROID RECEPTORS TRANSLOCATE INTO THE NUCLEUS AND INTERACT WITH GRE’S, OTHER HRE’s AND COACTIVATOR MOLECULES REGULATION OF TRANSCRIPTION BY NON-STEROIDAL HORMONES - NUCLEUS RX R N HRE NO HORMONES NO TRANSCRIPTION HORMONE-RESPONSIVE HORMONE-RESPONSIVE TARGET GENES TARGET GENES C RETINOID X RECEPTOR SUBUNIT (RX) REPRESSES TRANSCRIPTIONAL ACTIVATION BY HORMONE RECEPTOR (R) PLUS HORMONES NUCLEUS + VITAMIN D RETINOIC ACID THYROID HORMONE HRE TRANSCRIPTION HORMONE-RESPONSIVE TARGET GENES HORMONE BINDING RELIEVES REPRESSION BY RETINOID X RECEPTOR TRANSDUCER COMPLEX MESSENGER CASCADE TRANSCRIPTION PERMEABILITY ONE SIGNAL - MANY EFFECTS SAME HORMONE MAY HAVE DISTINCT EFFECTS IN DIFFERENT TISSUES OR CELL TYPES TRANSCRIPTION PERMEABILITY MANY SIGNALS - ONE EFFECT EFFECTS ON CELL FUNCTION MAY ONLY OCCUR IF CORRECT COMBINATION OF HORMONES ACT SIMULTANEOUSLY ON SAME , CELL TRANSDUCER COMPLEXES METABOLISM TRANSDUCER COMPLEXES MESSENGER CASCADES SECRETION EFFECTS ON CELLULAR FUNCTION TRANSCRIPTION G PROTEIN: ADENYLYL CYCLASE G PROTEIN: PLC RECEPTOR TYROSINE KINASE: PLCγ RECEPTOR TYROSINE KINASE: IRS-1 RECEPTOR TYROSINE KINASE: Grb2-SoS non-RECEPTOR TYROSINE KINASE (JAK) “2ND MESSENGER” CASCADES cAMP PROTEIN KINASE A 1,2- DAG PROTEIN KINASE C 1P3 Ca2+ CALMODULIN Ras: MAP KINASE OTHER IMPORTANT FEATURES 1. AMPLIFICATION BY ENZYMES OR ION CHANNELS 2.“CROSS-TALK” BETWEEN PATHWAYS 3. RAPID DEGRADATION/ DEACTIVATION OF 2ND MESSENGERS STIMULUS INDUCED DIMERIZATION EGF/ PDGF G-PROTEIN COUPLED EGF/PDGF TSH BINDING SITE PDGF SH2 DOMAINS PDGF CELL MEMBRANE CELL MEMBRANE SMALL LIGAND BINDING SITE ACCOMODATES CATECHOLAMINES P G-PROTEIN P P P DESENSITIZATION BY -ark or pkc Autophosphorylation by intrinsic tyrosine kinase THE INSULIN RECEPTOR IS A STABLE S-S LINKED DIMER GROWTH HORMONE AND PROLACTIN RECEPTORS ARE LIGAND-INDUCED DIMERS S-S -S-S- -S-S- IRS-1 TYROSINE KINASE (JAK2) Stat IGF-1 USES A SIMILAR MECHANISM Stat 5A DEFICIENT MICE DO NOT LACTATE GROWTH FACTOR RECPTOR SIGNAL TRANSDUCTION FROM CELL SURFACE RECEPTORS TO THE NUCLEUS TYROSINE PHOSPHORYLATION OF RECEPTOR RECRUITS Grb2-Sos TO PLASMA MEMBRANE PROTEIN KINASE C GTP Ras ATP MAPKKK ADP ATP MAPKK ADP GDP ACTIVATION OF Ras BY GUANINE NUCLEOTIDE EXCHANGE FACTOR Raf/MAPKKK ACTIVATED BY RAS OR PROTEIN KINASE C ACTIVATION OF MAP- KINASE REQUIRES BOTH THREONINE AND TYROSINE PHOSPHORYLATION MAPK NUCLEUS PHOSPHORYLATION OF TRANSCRIPTION FACTORS IN NUCLEUS RECEPTOR ACTIVATION HETEROTRIMERIC G PROTEINS CYCLASE ACTIVATION γ γ GTP GDP GTP Pi NUCLEOTIDE EXCHANGE GDP HIGH INTRINSIC GTPase = RAPID DEACTIVATION ATP cAMP Ras AND OTHER SMALL G PROTEINS SIGNAL IN GTP Sos GDP NUCLEOTIDE EXCHANGE GTP Ras (inactive) Ras GDP (active) LOW INTRINSIC GTPase GAP GTPase Activating Protein SIGNAL OUT MULTIPLE ROLES OF INTRACELLULAR CALCIUM IONS LIGAND-GATED PI-LINKED CALCIUM CHANNEL RECEPTOR VOLTAGE-SENSITIVE CALCIUM CHANNEL G PROTEIN PLC Ca2+ Ca2+ IP3 CALCIUM IS “STORED” PIP2 IN THE ENDOPLASMIC RETICULUM 2+ Ca /CALMODULIN MYOSIN LIGHT CHAIN KINASE (MLCK) PHOSPHORYLASE KINASE MYOSIN LIGHT CHAIN PHOSPHORYLASE EUKARYOTIC ELONGATION FACTOR II CAM KINASE 3 MULTIFUNCTIONAL CAM KINASES HO HO PLC 4 3 5 2 6 1 P OH 4 3 2 5 P INOSITOL 1,4,5-TRISPHOSPHATE IP3 6 1 HYDROLYSIS HO PHOSPHATIDYLINOSITOLS ARE HYDROLYSED BY PHOSPHOLIPASE C INTO TWO SECOND MESSENGERS 1,2-DIACYLGLYCEROL PHOSPHATIDYLINOSITOL PI-4P PI PI-4,5P2 4 4-KINASE 3 5 3 5 2 6 2 6 1 1 P P P 4 PI-3,4,5P3 5-KINASE 4 3 5 2 1 P P 4 3 5 2 6 PI-3KINASE 6 1 P 1,2-DAG PI 3,4 -P2 PHOSPHATIDYLINOSITOL CYCLE PROTEIN KINASE C ACTIVATION PHOSPHOLIPASE C (PLC) MEDIATED PI HYDROLYSIS IS STIMULATED BY MANY HORMONES PI 3,4,5-P3 PI 3-KINASE INSULIN ACTION PI PI 4-P PLC PI 4,5-P2 PHOSPHORYLATION RESYNTHESIS DEGRADATION I Li + Li + BLOCKS RESYNTHESIS IP IP2 CALCIUM RELEASE FROM ER VIA LIGAND GATED CHANNEL IP3 PHOSPHOLIPASE C ISOFORMS PLC N PH X EF Y C CATALYTIC SITES REGULATED BY Gq PLC N PH EF X SH2 SH2 SH3 Y C REGULATED BY TYROSINE PHOSPHORYLATION PLC N PH EF X Y C CATALYTIC SITES REGULATED BY Gq SEQUENCE MOTIFS INVOLVED IN SIGNAL TRANSDUCTION DOMAIN NAME MOTIF RECOGNIZED src homology 2 SH2 pY-X-X-X “phosphotyrosine-binding” PTB - ψ -N-P-X-pY- src homology 3 SH3 “proline-rich region” Pleckstrin Homology PH PI-Px headgroups Ψ =Hydrophobic residue PROTEIN ARRANGEMENT OF BINDING DOMAINS AND CATALYTIC SITES src kinase --Myr----SH3----SH3----SH2----Tyr kinase--- Btk Shc --PH----Pro----SH3----SH2----Tyr kinase-----PTB----SH2- (‘Collagen-like’) Grb-2 --SH3----SH2----SH3 Shp-2 (Syp) --SH2----SH2----PTPase PLC PLC ? --PH----PLC----PLC-- PLC --PH----PLC----SH2----SH2----SH3----PLC PLC --PH----PLC----PLC PKB --PH---- Ser/Thr kinase p120Ras-GAP --SH2----SH3----SH2----PH----GAP LECTURE 3 INSULIN RECEPTOR SIGNALING PATHWAY GLUCOSE UPTAKE INSULIN PDK GLUT4 TRANSLOCATION IRS-1 PY PI 3-KINASE INHIBITORS e.g. WORTMANNIN BLOCK GLUCOSE UPTAKE PY GSK3 SH2 PI 3-KINASE INHIBITION OF LIPOLYSIS FATTY ACID SYNTHESIS GLYCOGEN GENE EXPRESSION SYNTHESIS SYNTHESIS AND SECRETION OF PEPTIDE HORMONES 9. INCREASED HORMONE SYNTHESIS 1.TRANSCRIPTION AFTER CHRONIC STIMULATION AGONIST 2. ALTERNATIVE SPLICING NUCLEUS mRNA Ca2+ ENDOPLASMIC RETICULUM 3. TRANSLATION 4. TRANSLOCATION 5. TISSUE-DEPENDENT PROTEOLYTIC PROCESSING. 6. PACKAGING (200X CONDENSATION) INTO SECRETORY VESICLES 7. SECRETORY VESICLES ACCUMULATE CLOSE TO PLASMA MEMBRANE REGULATION OF PLASMA GLUCOSE BY INSULIN AND GLUCAGON Pglucose Pglucose GLUCOSE: PANCREAS cell - SYNTHESIS INSULIN SECRETION INSULIN t½ approx 5 min - MOBILIZATION PARACRINE INHIBITION OF ISLETS OF LANGERHANS BY INSULIN GLUCOSE: - UPTAKE GLUCAGON t½ approx 10 min GLUCAGON SECRETION PANCREAS cell TARGET TISSUES (liver, muscle, adipose, etc.) - UTILIZATION - STORAGE 1 MILLION ISLETS EACH CONTAINING 2500 CELLS BLOOD FLOWS RADIALLY FROM CENTER OF ISLET TO THE PERIPHERY FACILITATING PARACRINE INHIBITION OF GLUCAGON SECRETION BY INSULIN CORE FORMED BY BETA CELLS SECRETING INSULIN (60-70 % OF TOTAL) MANTLE FORMED BY CELLS SECRETING GLUCAGON (20-25%) ARTERIAL BLOOD CELL Canaliculus ISLETS OF LANGERHANS CELL SECRETORY GRANULES VENOUS BLOOD BLOOD VENOUS PHYSIOLOGICAL ROLE OF INSULIN MAINTENANCE OF NORMAL PLASMA GLUCOSE LEVELS IN SPITE OF LARGE CHANGES DUE TO FOOD INTAKE RAPID UPTAKE OF DIETARY GLUCOSE STIMULATION OF GLUCOSE TRANSPORT STIMULATION OF GLUCOSE UTILIZATION UTILIZATION OF DIETARY GLUCOSE STIMULATION OF GLYCOGEN SYNTHESIS STIMULATION OF GLUCOSE OXIDATION STIMULATION OF LIPID SYNTHESIS PRESERVATION OF ENERGY STORES INHIBITION OF GLYCOGEN DEGRADATION INHIBITION OF GLUCONEOGENESIS INHIBITION OF LIPOLYSIS INHIBITION OF PROTEOLYSIS K+ REGULATION OF INSULIN SECRETION BY GLUCOSE THESE CHANNELS ARE ALSO SENSITIVE TO OTHER STIMULI SUCH AS ACETYLCHOLINE AND CATECHOLAMINES - Ca2+ K+ ATP/ADP GLUCOSE OXIDATION Ca2+ Ca2+ INSULIN SECRETION GLYCOLYSIS GLUCOSE ATP GLUT2 KM >15mM UNLIKE HEXOKINASE, GLUCOKINASE IS NOT INHIBITED BY GLUCOSE-6-P GLUCOSE RESPONSE OF PLASMA GLUCOSE, GLUCAGON, ACTH AND GROWTH LEVELS TO INSULIN INJECTION 100 80 Pglucose ACTH 60 40 GROWTH HORMONE 20 0 30 INSULIN INJECTION 60 MINUTES 90 120 RESPONSE OF PLASMA INSULIN AND GLUCAGON TO ORAL GLUCOSE 180 POOR GLUCOSE TOLERANCE 150 120 90 Plasma glucose NORMAL GLUCOSE TOLERANCE AVERAGE VALUE plasma insulin 60 30 0 Plasma glucagon BELOW 60 mg/dl METABOLISM IS LIMITED BY GLUCOSE AVAILABILITY 1h 2h 3h 4h 5h TISSUE/PLASMA DISTRIBUTION OF GLUCOSE AFTER A MEAL PLASMA/ECF 10g/h 11g GLUT- 2 LIVER FOOD 75g GLYCOGEN 75-100g 6g/h GLUT- 1 7g/h 14g/h KIDNEY 0g/h GLUT- 4 URINE MUSCLE 300-400g GLUT- 4 ADIPOSE LIVER GLYCOGEN 75-100 g FED 7g/h GLUT- 2 BRAIN RBC’s 10g/h INSULIN LIVER INSULIN MUSCLE GLYCOGEN GLYCOGEN + + AFTER MEAL PROTEIN GLUCOSE GLUCOSE GLUT4 GLUCAGON GLUCOSE AMINO ACIDS GLUCOSE GLYCOGEN GLYCOGEN DURIN G FAST + GLUCOSE + ATP MUSCLE PROTEIN GLUCOSE-6-P PROTEOLYSIS GLUCONEOGENESIS LATE IN FAST~12-15h GLUT4 AMINO ACIDS GLUCOSE AMINO ACIDS CORTISOL HELPS TO MAINTAIN PLASMA GLUCOSE LEVELS DURING A FAST BY STIMULATING GLUCONEOGENESIS/LIPOLYSIS AND INHIBITING LIPID SYNTHESIS MUSCLE PROTEIN GLUT4 AMINO ACIDS FATTY ACIDS PROVIDE AN ABUNDANT SOURCE OF ENERGY BUT IN VERTEBRATES, (UNLIKE PLANTS),THEY CANNOT BE CONVERTED BACK TO GLUCOSE IN DIABETES THERE IS NO INSULIN TO INHIBIT THIS PROCESS PGLUCOSE FATTY ACIDS AMINO ACIDS GLUCONEOGENESIS LIPOLYSIS GLUCOSE LIVER GLYCOGEN FAT DROPLET FATTY ACIDS ADIPOSE DURING A FAST THE LIVER MOBILISES GLUCOSE STORED FAT IN ADIPOSE TISSUE AND CONVERTS IT TO KETOACIDS FOR EXPORT TO OTHER TISSUES LIVER KETONE BODY SYNTHESIS CAPILLARY ENDOTHELIUM HYDROLYSIS OF TRIGLYCERIDES TG FFA FFA FFA ACETYL CoA “KETONE FFA BODIES” MUSCLE HEART etc. ß-OXIDATION OF FATTY ACIDS TO ACETYL CoA FFA FFA FREE FATTY ACIDS (FFA) HAVE ADIPOSE TISSUE HYDROLYSIS OF STORED TRIGLYCERIDES (TG) BY LIPASE LOW SOLUBILITY AND ARE TRANSPORTED IN THE BLOOD BOUND TO ALBUMIN OR LIPOPROTEINS SMALL INTESTINE DIETARY GLUCOSE DIGESTION, ABSORPTION AND DIETARY FAT RESYNTHESIS OF TRIGLYCERIDES (TG) FFA TG AFTER A MEAL THE LIVER SYNTHESIZES FREE FATTY ACIDS (FFA) FROM GLUCOSE AND EXPORTS IT TO THE TISSUES AS TRIGLYCERIDES FFA GLUCOSE CAN BE CONVERTED TO FAT, BUT FAT CANNOT BE CONVERTED BACK TO GLUCOSE CAPILLARY ENDOTHELIUM HYDROLYSIS OF TRIGLYCERIDES LIVER FATTY ACID SYNTHESIS ACETYL CoA MUSCLE, HEART etc. ß OXIDATION OF FATTY ACIDS ADIPOSE TISSUE RESYNTHESIS AND STORAGE OF FFA ACETYL CoA TRIGLYCERIDES FFA REM Sleep Arginine exercise STRESS preREM Sleep REGULATION OF GROWTH HORMONE SECRETION PGLUCOSE + + - + - HYPOTHALAMUS THERE ARE 6 DISTINCT IGF BINDING PROTEINS IGFBP(1-6) . ONE OF THEM IS THE EXTRACELLULAR PORTION OF THE GH RECEPTOR SOMATOSTATIN / GHIH - + TRANSPORT IN BLOOD GHRH “SOMATOMEDIN” PITUITARY FREE IGF’s BOUND IGF’s GROWTH HORMONE BASAL GH 10-10M TOO LOW TO MEASURE ACCURATELY MANY TISSUES METABOLIC EFFECTS: INCREASED LIPOLYSIS AND PROTEIN SYNTHESIS DECREASED GLUCOSE USE “SOMATOMEDIN” GROWTH HORMONE IS SPECIES-SPECIFIC LIVER AND FIBROBLASTS IGF-1 AND IGF-2 SECRETION BONE AND CARTILAGE SKELETAL GROWTH EFFECTS HORMONAL REGULATION OF METABOLISM LIPOLYSIS PROTEIN DEGRADATION GLUCOSE SYNTHESIS LIVER GLYCOGEN PLASMA GLUCOSE (-1) ( ) ( ) INSULIN CORTISOL GLUCAGON GROWTH HORMONE CATECHOLAMINES LEPTIN ? REM Sleep STRESS + PGLUCOSE REGULATION OF ADRENAL HORMONE SECRETION + HYPOTHALAMUS “ADDISON’S DISEASE” DESTRUCTION OF THE ADRENAL GLAND BY DISEASE OR BY SURGICAL REMOVAL OF THE GLAND. THIS DISEASE IS LETHAL IF NOT TREATED BY HORMONE REPLACEMENT THERAPY - CORTISOL CRH + - PITUITARY ACTH TRANSPORT IN BLOOD BOUND STEROIDS (90%) FREE STEROIDS (10%) CORTISOL IS NOT STORED + CHOLESTEROL * ADRENAL CORTEX “ZONA FASCICULATA” ACTH STIMULATES STEROID SYNTHESIS WITHIN MINUTES DUE TO CHOLESTEROL ALREADY PRESENT IN MITOCHONDRIAL INNER MEMBRANE ALDOSTERONE STEROIDS ANDROGEN PRECURSORS LECTURE 4 CAPSULE MEDULLA RETICULARIS MEDULLA SECRETION OF INDIVIDUAL STEROID HORMONES IS RESTRICTED TO SPECIFIC REGIONS OF THE ADRENAL CORTEX ALL STEROIDOGENIC TISSUES STEROID SYNTHESIS CHOLESTEROL (C27) minus side chain + 20-keto GONADS PREGNENOLONE (C21) DEHYDROEPIANDROSTERONE SULFATE (C19 :“DHEA-S”) + 17-OH + 3-keto desmolase 17-OH PREGNENOLONE PROGESTERONE + 21-OH sulfotransferase DEHYDROEPIANDROSTERONE” ’’DHEA” + 17-OH + 3-keto + 3-keto desmolase + 11-OH CORTICOSTERONE + 18-ALDEHYDE 17-OH PROGESTERONE + 21-OH ANDROSTENEDIONE (C19) TESTOSTERONE aromatase + 11-OH +3-keto ALDOSTERONE (C21) ADRENAL CORTEX CORTISOL (C21) DIHYDROTESTOSTERONE (C19) ESTRONE aromatase ESTRADIOL (C19) SYNTHESIS AND “SECRETION” OF STEROID HORMONES BY ADRENAL CORTEX 1 UPTAKE OF CHOLESTEROL ESTER FROM LDL AND HDL IN PLASMA 2 CHOLESTEROL IS TAKEN UP INTO MITOCHONDRIA EITHER DIRECTLY FROM PLASMA LDL/HDL OR FROM INTRACELLULAR CHOLESTEROL ESTERS “STORED” IN LIPID DROPLETS StAR facilitates transfer of cholesterol molecules between inner and outer membranes KIDNEY ALDOSTERONE Cholesterol in Intracellular Lipid droplets DIFFUSION OF STEROIDS OUT OF CELL CORTISOL 4 P450c11 11-HYDROXYLASE REMOVAL OF SIDE CHAIN 17-OH PROGESTERONE ENDOPLASMIC RETICULUM 3 OXIDATION OF STEROID NUCLEUS BY SPECIFIC P-450 HYDROXYLASES ANDROGEN PRECURSORS GONADS 20 CHOLESTEROL 12 18 2 16 C 15 14 9 C H3 13 C 19 10 5-PREGNENOLONE 17 11 1 21 12 8 7 5 4 1 2 13 C 19 6 15 14 9 10 17 16 11 B 3 18 O 8 B C H3 17-OH PROGESTERONE 12 C 18 11 1 2 C 19 9 10 10 13 14 3 C H3 7 5 6 4 C O 12 OH 16 2 15 8 5 O 4 6 16 9 10 10 13 C 19 14 15 8 B B 7 18 11 1 O O 7 5 6 PROGESTERONE ANDROSTENEDIONE ESTRONE O 12 18 11 1 2 O 12 17 16 13 11 10 15 14 9 1 2 8 17 14 8 17 9 Aromatase 7 HO 6 7 5 6 4 OH OH 12 18 11 1 2 12 17 C 9 1 14 15 2 8 O TESTOSTERONE C 9 10 14 8 B 7 6 13 19 B 5 18 11 13 19 10 15 B 5 4 C 19 10 B OH 13 C 19 18 Aromatase HO 7 5 4 6 ESTRADIOL DIHYDROTESTOSTERONE 15 “PRE-RECEPTOR REGULATION” OF STEROID HORMONE ACTION 11ß-HYDROXYSTEROID DEHYDROGENASE - (11ß-HSD) 11ß- HSD TYPE 1 (LIVER) CORTISOL ACTIVE 12 OH 2 C 10 10 16 13 1 14 15 2 8 O 7 5 4 6 19 11 40 C 9 10 10 13 14 8 B B B 3 18 OH 19 9 OH O 12 18 11 11 1 CORTISONE INACTIVE CH20H C 11ß- HSD TYPE 2 (KIDNEY) 333 O 7 5 4 6 O OH 16 15 LOCAL DEHYDROGENATION OF THE C11 HYDROXYL GROUP ON CORTISOL PROTECTS MINERALOCORTICOID RECEPTORS (MR) FROM INAPPROPRIATE ACTIVATION ALDOSTERONE:MR CORTISOL or CORTISONE : MR CORTISOL or CORTISONE : GR Kd~1nM Kd~1nM Kd~10nM IN SPITE OF THE HIGH AFFINITY OF CORTISOL / CORTISONE FOR THE MR IN VITRO, GLUCOCORTICOIDS DO NOT BIND TO MR IN TARGET TISSUES. THIS IS DUE TO THE “PRE-RECEPTOR INACTIVATION” OF CORTISOL BY 11ß-HSD2 LIVER ADIPOSE GONADS CORTISOL CORTISOL 11ß-HSD1 11ß-HSD2 OXIDATION OF C11 HYDROXYL CORTISOL CORTISONE GR RESPONSE nucleus MR NO RESPONSE nucleus KIDNEY,COLON SALIVARY GLAND, HEART BINDING AFFINITIES OF STEROIDS TO PLASMA PROTEINS HORMONE CORTISOL CORTISOL BINDING PROTEIN (CBP) 76 CORTISONE 7.8 ESTRADIOL 0.06 PREGNENOLONE PROGESTERONE 17α -OH-PROGESTERONE TESTOSTERONE SEX HORMONE BINDING GLOBULIN (SHBG) 0.18 24 55 5.3 1.6 2.7 ALBUMIN 0.003 0.005 680 0.06 14 0.06 8.8 0.06 9.9 0.4 1600 0.04 SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION TYROSINE TYROSINE IODINATION MONOIODOTYROSINE (MIT) THYROGLOBULIN I THYROGLOBULIN Tyr Approximately 10% of the tyrosine residues on the 550 amino acid residue Thyroglobulin molecule may become iodinated by the enzyme - thyroid peroxidase acting on the colloid at the luminal surface of the thyroid follicle. These reactions only occur in the thyroid at specific residues in “Hormonogenic” sites located at the extreme ends of the Thyroglobulin molecule. TYROSINE IODINATION I DIIODOTYROSINE (DIT) - Tyr NH2 I THYROGLOBULIN SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES I HO I CH2CHCOOH Tyr I HO 5’ + HO Tyr CH2CHCOOH HO I Tyr O Tyr 3 T4 I Thyroglobulin Thyroglobulin 5 3’ NH2 NH2 I II I 3,5,3’5’-tetraiodothyronine I Coupling of iodotyrosine moities results in the loss of the peptide linkage to thyroglobulin allowing thyroid hormones to diffuse across the cell membrane 3,5,3’-Triiodothyronine I Tyr HO CH2CHCOOH + Tyr CH2CHCOOH NH2 NH2 HO Tyr O Tyr I I Thyroglobulin Thyroglobulin I T3 I 3,5,3’5’-tetraiodothyronine STEP 3 DEIODINATION I I O Tyr CH2CHCOOH Tyr NH2 “DEACTIVATION” PATHWAY I T4 I 5’- deiodination 5-deiodination rT3 I Tyr O “ACTIVATION” PATHWAY SELENODEIODINASES I T3 I Tyr CH2CHCOOH Tyr I O Tyr NH2 I 3,3’,5’-Triiodothyronine (reverse T3) CH2CHCOOH NH2 I 3,5,3’-Triiodothyronine (T3) SECRETION OF THYROID HORMONE 4 IODINATION OF THYROGLOBULIN BY THYROID PEROXIDASE TG 3 TG TG I ENDOCYTOSIS OF ‘COLLOID’ IN FOLLICLE BY PSEUDOPOD 5 FUSION OF PHAGOSOME WITH LYSOSOMES TG DEGRADATION AND RECYCLING OF MIT/DIT BY DEIODINASES 6 TG DEGRADATION OF THYROGLOBULIN 7 T4 2 FREE THYROXINE RELEASED FROM PROTEIN INTO CYTOPLASM 8 IODIDE UPTAKE BY Na/I SYMPORTER “DIFFUSION” OF THYROXINE THROUGH CELL MEMBRANE T4> > > T3 1 IODIDE IN ECF~20nM Additional metabolism?? THYROID HORMONES HORMONE T4 T3 rT3 * RELATIVE POTENCY + ++++ - PRODUCTION PLASMA CONCENTRATION (µg/day) (µg/dL) 80- 90 8 4-8 (24)* 2-3 (27) * BOUND TO PLASMA PROTEINS (%) 99.95 t½ (days) 6-7 0.3 99.7 1-3 0.04 99.8 0.1 VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION EFFECTS OF THYROID HORMONE ON TARGET TISSUES MOST EFFECTS OF THYROID HORMONE ARE “PERMISSIVE”: THYROID HORMONE PROMOTES SYNTHESIS OF PROTEINS WHICH ARE THEN REGULATED ACUTELY BY OTHER HORMONES. THYROID DISEASES METABOLISM THYROID HORMONE INCREASES: BASAL METABOLIC RATE BODY TEMPERATURE CARDIAC OUTPUT/ TACHYCARDIA MOBILIZATION OF ENERGY STORES GROWTH AND DEVELOPMENT THYROID HORMONE REQUIRED IN PERINATAL PERIOD FOR: NEURAL DEVELOPMENT BONE GROWTH (GH) CONGENITAL HYPOTHYROIDISM DUE TO “METABOLIC” DEFECT IN THYROID HORMONE SYNTHESIS RESULTING IN MENTAL RETARDATION UNCOMMON IN DEVELOPED COUNTRIES DUE TO EARLY POST- NATAL TESTING “ENDEMIC” HYPOTHYROIDISM DUE TO IODIDE DEFICENCY OR GOITROGENS. READILY PREVENTED BY IODIDE SUPPLEMENTATION OF FOOD HYPERTHYROIDISM AUTOIMMUNE “GRAVES DISEASE” PITUITARY TUMOR THYROID TUMOR WEIGHT LOSS THYROID DISEASES DISEASE TYPE CONGENITAL IODIDE DEFICIENCY AUTOIMMUNE: THYROIDITIS AUTOIMMUNE: GRAVES DISEASE THYROID SERUM STATUS HYPO HYPO HYPO T3 +T4 LOW LOW LOW SERUM TSH HIGH HIGH HIGH CAUSE OF DISEASE DEFECT IN IODIDE TRAP OR THYROID HORMONE SYNTHESIS DIET: (i) LOW IN IODIDE OR (ii) GOITROGENS PRESENT DESTRUCTION OF THYROID TISSUE DUE TO INFLAMMATION AUTOANTIBODIES TO THE TSH HYPER HIGH LOW RECEPTOR PROVIDE CONTINUOUS UNREGULATED STIMULUS THYROID TUMOR HYPER HIGH LOW PITUITARY TUMOR HYPER HIGH HIGH UNREGULATED SYNTHESIS AND SECRETION OF T3 AND T4 UNREGULATED SYNTHESIS AND SECRETION OF TSH CALCIUM IN DIET PLASMA Ca2+ CALCIUM SENSOR DECREASE IN PLASMA CALCIUM STIMULATES PARATHYROID HORMONE (PTH) SECRETION PTH CHOLESTEROL PARATHYROID VITAMIN D3 PTH 25-(OH)-D3 PO4 BONE KIDNEY 1,25-(OH)2-D3 Ca2+ CALCIUM REABSORPTION PHOSPHATE EXCRETION Ca2+ INCREASE IN PLASMA CALCIUM STIMULATES CALCITONIN SECRETION FROM THYROID PARAFOLLICULAR CELLS PLASMA Ca2+ URINE PO4 GUT 100 % MAXIMAL PTH RESPONSE PTH SECRETION EXHIBITS A STEEP INVERSE SIGMOIDAL DEPENDENCE ON EXTRACELLULAR Ca2+ INCREASED Ca2+ SUPRESSES PTH SECRETION VIA A G PROTEIN COUPLED MECHANISM 50 0 1.0 1.25 IONIZED CALCIUM (mM) 1.5 CALCITONIN IS SECRETED FROM THE THYROID PARAFOLLICULAR CELLS BUT IS CALCITONIN AN IMPORTANT PHYSIOLOGICAL SUBSTANCE? The observation that calcitonin (CT) at supraphysiological doses is hypocalcemic, led to the mistaken conclusion that it was important for calcium homeostasis and this idea has persisted to this day. Despite these findings there is no readily apparent pathology due to CT excess or deficiency and there is no evidence that circulating CT is of substantial benefit to any mammal. ……….. . Mammalian CT at physiological doses is not essential and very likely the CT gene has survived because of the gene’s alternate mRNA pathway to produce calcitonin-gene-related peptide found in neural tissues. HIRSCH,PF and BARUCH H, ENDOCRINE 2003, 201-208