PGY452 552 Endocrine physiology 3 Regulation of hormone activity A B C D Hormone synthesis release Persistence of hormone action Target level regulation Feedback regulation Regulation of hormone activity Hormones Signals Hormone 3 4 5 H 2 Hormone synthesis release Persistence Target Feedback Input H H 1 H H Regulation key to homeostasis Mechanisms H Input Covered H H H H H Response 2 A Regulation of hormone synthesis release Synthesis All hormones Release Only proteins 3 Levels of all hormones are regulated by gene expression Gene Pol II Transcriptional regulation AAAAAAAAAAA Steroid hormones Protein hormones AAAAAAAAAAA H mRNA Direct preprohormone AAAAAAAAAAA Indirect Steroidogenic cytochromes P450 4 Regulatory points unique to steroid hormone Steroid acute regulatory synthesis LDL R protein Cytochrome P450 side chain cleavage Unique biosynthetic enzymes LDL receptors Unique enzyme StAR Unique enzyme P450SCC SCC PKA PKC StAR P450SCC Fast kinase Slow transcription PKA PKC P Pol II 5 Regulatory points unique to protein hormone synthesis 1 Transcription of the hormone gene 2 Exocytosis of stored vesicles 3 Proteases in the blood stream rare blood ECF 3 Fast 1 Slow AAAAAA Pol II 2 Fast Universal 6 Vesicle release is THE critical step in protein hormone regulation H Fast seconds Main stimuli Ca2 G q IP3 Other stimuli Ca2 channels Mechanisms H Direct activation of release Ca2 activated Ca2 release Distinction not important G s PKA Amount of hormone available for release regulated by transcription 7 H H GnRH pg mL H H Regulation of exocytosis results in pulsatile release Simultaneous vesicle 35 release 30 25 Many vesicles in 20 each cell 15 10 Not all released at 5 0 once 0 120 240 360 480 H HH H H H H H H HH H H H H H H HHH H H H H H H HH H H H HH H H H H H H HH H H HH H H H H H H H HH H HH H HH H H H H H H H HH H H H H H HH H HH H HH HH H H H H H H H HH H H HH H H H H HH H H HHH H H H H H H H H H H H H H H H H H H Time min H HH H H H H HH HH H H HH H H H H H H H H H H H H H H HH H H HH H H H HHH H H HH H H H HH H H H H H HHH H H H HHH H HH HHH H H H HH H HH H H HH H H H H H H H HHH H H H HHH H H H HHH H H H H H H H H H HH H H H HHH H H H H HH HH H H H HH H HH H H H HHH H H H H HHH H H H H H H H HH H H H H HH H H HHH H H H H HH H H H HHH H H H H H H H H HHH H H H H HH H HH H H H H H HH H HH H H H HHH HH H H H H HHH H H H H H H H H HHH H H H H H H H HHH Input H H HH H HH HH H H H H H H Input strength determines amplitude release New vesicles require transcription SLOW H H 8 Regulation by specific bloodstream proteases Peptides only Inactive prohormone Only a couple examples not common Active hormones Inactive peptide fragments Protease Activate Inactivate 9 B Regulation by persistence The length of time a hormone lasts in the blood stream before disposal 10 Measuring persistence 500 min 100 90 Half life The time it takes for the concentration of a hormone to decrease by half t Steroids Proteins Considerable overlap Small proteins Large Glycoproteins Protein hormone binding proteins t Log amino acid number 80 70 60 60 min 50 40 30 20 5 min 10 0 0 50 100 150 200 250 300 Time min Peptides BP 3500 Glycoproteins 350 35 Amides Steroids 3 5 0 35 1 10 100 Log time min 1000 11 Protein hormone half life Small amount taken up by target tissues Mostly renal filtration Small proteins Large proteins Endocytosis at luminal membrane Metabolized to amino acids H H H H amino acids H H lumen apical basolateral Some have specific uptake receptors t venous 12 Steroid hormone inactivation by metabolism Enzymatic modification Phase 1 modification cortisol allotetrahydrocortisone progesterone pregnanediol 3 glucuronide Testosterone Etiocholanolone 3 sufate Phase 2 conjugation Hydroxylation Oxidation Reduction Glucuranation Sulfation Often 1 pathway Make soluble Cytochromes P450 13 Steroid metabolism allows clearance Other tissues Metabolized elsewhere Metabolized in the liver Excreted Circulating steroid hormone Eliminate d with bile 14 Hormone concentration ranges Response strength determined by Hormone concentration Hormone efficacy EC50 Hormones are never zero NO ON OFF switches Narrow range Concentrations Steroids glycoproteins peptides log concentration pM 0 1 10 100 1 000 10 000 100 000 1 000 000 Peptides Glycoproteins Steroids Insulin Glucagon ACTH Calcitonin TSH inhibin FSH Cortisol Testosterone Estradiol Estradiol 15 Concentration is local Target2 Gland Target3 Target1 Target2 Target3 Small gland low concentration limited response Target3 Large gland high concentration broad response Small Target1 Target2 LARGE Target1 Response reflects Hormone 16 Gland size important predictor of hormone concentration Big glands lots of hormone Pineal gland Hypothalamus Posterior pituitary Anterior pituitary Skin Parathyroid glands Heart Liver Steroids always come from big glands Proteins often from small glands or few cells in secondary endocrine tissue Adrenal cortex Adipose tissue Kidneys Pancreas Stomach small intestine Testes Ovaries Blastocyst Placenta 17 Hormone amount per unit volume Interstitial Fluid hormone mole liter Lots of trivial units Liter of Extracellular fluid Blood Plasma Blood plasma Interstitial fluid Plasma blood stream ECF are often used interchangeably Measurement is local may be different elsewhere Complicated by Circadian release Pulsatile release Short half lives 18 C Target level regulation Receptor expression Relationships between multiple hormones 19 Receptor diversity dictates target response 1 Receptor Hormones can have many Skeletal muscle blood vessel Intestinal blood vessel Targets Responses 1 receptor hormone Tissue specific Example the amide hormone epinephrine 2 Receptor Epi Constriction Dilation 20 Multiple hormones at the target Most targets receptors for many hormones Relationships Antagonism Two hormones with opposite effects Synergism The sum is greater than individual effects Insulin vs glucagon Growth hormone releasing hormone vs somatostatin Parathyroid hormone vs calcitonin Different signaling mechanisms Cortisol glucagon Testosterone estradiol Permissiveness Full effect of one hormone requires presence of another Epinephrine Thyroid hormone 21 C Feedback regulation All hormones are regulated by feedback o Negative o Positive Homeostasis Feedback is one of the most important ideas in all of biology Claude Bernard 1813 1878 from page 576 of An Introduction to the History of Medicine by Fielding Hudson Garrison 1917 22 Most hormones are regulated by negative feedback