Principles of Hormonal Integration. Principles of Hormonal Integration

Transcription

1 Review #2 16 Review using OPAL figures Review using class web PDF Review using test #1 Preview of test #2 Review #2 16 ndocrinological solutions to physiological problems require integration of a large variety of simultaneous events Redundancy, is the excess of regulatory capacity provided in the form of seemingly duplicative or overlapping controls Reinforcement, most hormones act at several locales either within a single cell or in different tissues or organs to produce separate but mutually reinforcing responses Push-pull, many critical processes are under dual control by agents that act antagonistically either to stimulate or to inhibit Modulation of responding systems, or the relationship between amount of hormone available and magnitude of the response, is subjected to regulation by many factors, including the action of other hormones 1

2 Introduction story lines and circles within circles within (how many circles? Redundancy, is the excess of regulatory capacity provided in the form of seemingly duplicative or overlapping controls Redundancy allows for physiological adaptation when partial or even total failure of an homeostatic mechanism occur and another compensates for it trategies for therapeutic interventions, designed to increase or decrease the rate of a process, must take into account the redundant inputs that regulate that process Redundancy allows for adaptation of homeostatic to confront environmental changes 2

3 (e.g. at a tissue level) Glucagon and epinephrin, two hormones from two different tissues, produce the same end-result (e.g. at a molecular level) pinephrin increase glycogenolysis by two signal transduction pathways to produce a same endresult 3

4 (e.g. at different time domains at the same site) pi and GH increase plasma FFA at two different time - domains for acute and susteined responses (e.g. at different time domains at different sites) PTH and Vit D increase blood levels of calcium at different target sites and at different time-domains 4

5 (e.g. at the same time domain from different sites) GH and dexamethason increase lipolysis in a synergistic way when administered simultaneously Reinforcement, most hormones act at several locales either within a single cell or in different tissues or organs to produce separate but mutually reinforcing responses from the perspective of the whole organism. For example: Insulin has different effects in different ICF and CF places regarding fat storage Cortisol has different effects in different places of different cells regarding gluconeogenesis. Aldosterone has different effect in different places of a single cell regarding Na reabsorption Reinforcement involves multiple target homeostatic activation to confront environmental changes 5

6 glycogen phosphorilase glucose amino acids proteins G-6-Pase F-1,6-diPase transaminases glycogen glycogen synthetase G P hexokinase G P glucose F P PFK F - 1,6 -dip triose pyruvate Krebs cycle insulin glucagon epinephrine glucocorticoids acetyl CoA fats Insulin has different effects in different ICF and CF places regarding fat storage Insulin has different effects in different ICF and CF places regarding fat storage 6

7 Increased uptake of glucose which serves as substrate for fatty acid synthesis and for alphaglycerol phosphate to trap any FFA formed by spontaneous lipolysis of triglyceride stores Activate enzymes for fatty acid synthesis (e.g. pyruvate dehydrogenase, pyruvate carboxylase, acetyl-coa carboxylase) Inhibits breakdown of triglycerides already made Induced synthesis of the CF enzyme lipoprotein lipase needed to take-up lipids from circulation Insulin has different effects in different ICF and CF places regarding fat storage glycogen phosphorilase glucose amino acids proteins G-6-Pase F-1,6-diPase transaminases glycogen glycogen synthetase G P hexokinase G P glucose F P PFK F - 1,6 -dip triose pyruvate Krebs cycle insulin glucagon epinephrine glucocorticoids acetyl CoA fats Cortisol has different effects in different places of different cells regarding gluconeogenesis 7

8 Cortisol has different effects in different places of different cells regarding gluconeogenesis Glucocorticoids promote protein breakdown in muscle and lymphoid tissues and consequently release of aminoacids into the blood In adipose tissue, glucocorticoids promote triglyceride lipolysis and the release of glycerol In the liver, glucocorticoids induce the formation of the enzymes necessary to convert aminoacids, glycerol and other substrates into glucose Cortisol has different effects in different places of different cells regarding gluconeogenesis 8

9 serosal surface luminal surface ALDO " "its mechanism of action include: " " 1) increase Na permeability " 2) "increase content of Na/ K ATPases" " 3) "increases ATP to Na / K ATPases" " Aldosterone has different effect in different places of a single cell regarding Na reabsorption Many critical processes are under dual control by agents that act antagonistically either to stimulate or to inhibit. uch dual control allows for a more precise regulation than through negative feedback Insulin and glucagon form a push-pull mechanism controlling glucose output from liver which under basal catabolic and anabolic conditions is controlled by their negative feedbacks. In emergency situations or during exercise pi and Nepi release from adrenal medulla and sympathetic nerve endings overide them Another example of a push-pull mechanism is the switch operated by glycogen phosphorylase and glycogen synthetase, through their simultaneous camp activation and inactivation by glucagon and insulin, as well as by other hormones such as pi Push-pull allow for a more precise regulation than that produced by negative feedback 9

10 Insulin and glucagon form a push-pull mechanism controlling glucose output from liver AVP Insulin released and glucagon from form the a PP push-pull controls mechanism water controlling glucose output from liver 10

11 Insulin AVP released and glucagon from form the a push-pull PP controls mechanism wate controlling glucose output from liver AVP released from the PP controls wat Insulin and glucagon form a push-pull mechanism controlling glucose output from liver 11

12 Modulation of responding systems, or the relationship between amount of hormone available and magnitude of the response, is subjected to regulation by many factors, including the action of other hormones Two important determinants of the magnitude and the duration of responses are the hormone concentration present in the CF sourrounding a target site and the length of time that concentration is maintained. For hormones having pulsatile release it means frequency and amplitude of the hormone pulsatile release Another important determinant of the magnitude and the duration of the response are the sensitivity of target tissues to hormonal stimulation and their capacity to respond. Neither of them is constant and can be modulated by other hormones Modulation of responding systems relates to amount of hormone available and magnitude of the response Modulation of responding systems relates to amount of hormone available and magnitude of the response 12

13 k1 H + R <------> H R H * R H R = catchard plot bound / free H R / H k2 k1 k2 bound hormone ( H R ) = kd single binding slope = - 1 / kd capacity binding capacity half saturation affinity = kd free hormone ( H ) double binding bound hormone ( HR ) high affinity / low capacity low affinity / high capacity A lower Km (response at half maximal velocity) indicates the sensitivity of hormone-receptor binding modulation of sensitivity A lower Km (response at half maximal velocity) indicates the sensitivity of hormone-receptor binding 13

14 modulation of sensitivity change in Vmax when Km is maintained indicates changes in the capacity of the system to respond modulation of sensitivity main modulation paradigm is change of receptor # rather than receptor affinity by covalent modification 14

15 post-receptor effects number of occupied receptors per cell x 1000 biological response as % of maximum pecific hormone binding Biological response hormone concentration (M) % reduction in the conc. of receptors pare receptors, if fewer than 100% of receptors are occupied to reach the maximal biological response number of receptors occupied for maximal biological response (100%) post-receptor effects pare receptors, if fewer than 100% of receptors are occupied to reach the maximal biological response 15

16 2 LH -Fb +Fb POA abundance of competent target cells phasic control of 2 on the preovulatory LH surge is related to the increase abundance of granulosa cells permissive actions R Na / K pump camp ----> PKA ----> channel / enzyme AC Protein synthesis teroid + R ----> R XX1 HR mrna R DNA addi tional transc ription factor pare receptors, if fewer than 100% of receptors are occupied to reach the maximal biological response 16

17 Review #2 16 Review using OPAL figures Review using class web PDF Review using test #1 Preview of test #2 The Adrenal Gland 17

18 The Adrenal Medulla pinephrine Actions Increase mental alertness Increase glycogenolysis Increase lipolysis Relaxation of GI & urinary bladder smooth muscle Relaxation of smooth muscle of lung airways - dilation Rise glucagon and lower insulin secretion Increase CO (V& HR), vasodilation in skeletal muscle, vasoconstriction in internal organs & skin 18

19 pinephrine Metabolic Actions ndocrine Pancreas 19

20 ndocrine Pancreas ndocrine Pancreas 20

21 Cortisol a Glucocorticoid Growth Hormone (GH) 21

22 Aldosterone a Mineralocorticoid Review #2 16 Review using OPAL figures Review using class web PDF Review using test #1 Preview of test #2 22

23 Catecholamines Catecholamines, AN, pi, Nepi, DA!! " a) "Cas and the AN" " b) "pi" " c) "Nepi / DA" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others GI Regulating Hormones!GI regulating hormones, gastrin family,!!ecretin family, PP family, others!! " a) "Gastrin" " b) "ecretin, CCK" " c) "GLP-1" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others 23

24 Pancreas and its Hormones!Pancreas and its hormones regulating intermediary metabolism!! " a) "Insulin" " b) "Glucagon" " c) "omatostatin" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" teroid Hormones teroid hormones, origin, metabolism, neurosteroids! " a) "mineralocorticoids" " b) "glucocorticoids" " c) "gonadal steroids" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" 24

25 Glucocorticoids!Glucocorticoids & its regulating hormones, cortisol, ACTH, CRH! " a) "cortisol" " b) "ACTH" " c) "CRH" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" Growth and its Hormones!Growth & its regulating hormones,!!gh, IGFs, GHRH,, growth factors!! " a) "GH" " b) "IGFs and other growth factors" " c) "GHRH, " (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others 25

26 Mineralocorticoids!Mineralocorticoids & its regulating hormones, aldosterone, renin, Ang II!! " a) "aldosterone" " b) "renin " " c) "angiotensin II" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" Review #2 16 Review using OPAL figures Review using class web PDF Review using test #1 Preview of test #2 26

27 e.g. sentences from website 1 ome basic endocrine concepts and the methodologies used to study a) "definition of hormone and of endocrine, neurocrine, paracrine transmission" b) "methodologies used in endocrinology (RIAs, RRA, ICC, hybridization,!)" c) "how liposoluble and watersoluble hormones are made in general (R vs RR)" d) "hormone story line as a trick! to think of steps involved in hormone function" 2! A story line! table for all hormones. Things to look up in the table! a) "hormones that are water soluble and those that are lipo soluble" b) "hormones involved in hierarchies (gonadal, adrenal, thyroid!)" c) "hormones involved in metabolism (glucose, calcium, sodium, water)" d) "inputs to endocrine glands and hormone effects on different organs" 3!Reflex-arc! like-models and the!- Fb! for different hormones! a) "inputs, integrators, -Fb in the control of different hormones (the refrigerator)" b) "role of the hypothalamus in neuroendocrine control of the endocrine system" c) "theoretical components of a control system, homeostasis and rheostasis" d) "endocrine and neuroendocrine control and their disruption in pathology" 4 ome basic points on mechanism of action of liposoluble hormones a) "intracellular receptors mainly! but also membrane receptors (experiments)" b) "effect on protein synthesis mainly,! but some also have membrane receptors" c) "cys and trans elements involved in regulation at the promoter level.. integrator" d) "permissive effects of some liposoluble hormones (e.g. T3-4, Cortisol, 2,!)" " e.g. sentences from website 5 ome basic points on mechanism of action of water soluble hormones a) "plasma membrane receptors! but they also have access to the genome" b) "an ultimate effect on channels and enzymes underlies endocrine action" c) "GPCR and Tyr-kinase links, different paths to protein phosphorylation" d) "Permissive effects of some watersoluble hormones (e.g. Prl on LH receptors)" 6 ome basic points on the hypothalamic pituitary connection! a) "hypothalamic anterior pituitary portal system (neurohormones, amplification)" b) "hypothalamic posterior pituitary system (a good example of neuronal events)" c) "the pituitary receives 2/3 of the outputs from PVN (a main brain integrator)" d) "the median eminence as a final brain integrator site for endocrine function" 7 ome basic points on anterior pituitary (AP) hormones a) "most AP hormones are tropic / trophic hormones that act on other endocrine glands" b) "all AP hormones are controlled by hypothalamic hypophysiotropic neurohormones" c) "the hypothalamic AP unit acts as an integrator and amplification control unit" d) "the hypothalamic AP link is a vascular one since both tissues have different origin" 8!ome basic points on posterior pituitary (PP) and pineal hormones! a) "PP hormones are neurohormones made in the hypothalamus and released in the PP" b) "the hypothalamus and PP have the same embryological origin (as opposed to AP)" c) "PP hormones are involved in water metabolism and myoepithelial contraction" d) "AVP is also released in M and acts in AP as a CRH, albeit by different mechanism" " 27

28 e.g. sentences from website 9 AVP, OT, and melatonin a) "AP hormones (ACTH, GH, PRL, TH, LH, FH, MH, ND) " "see below (*)" b) "PP hormones (AVP, OT) " " " "see below (*)" c) "Pineal hormone (Melatonin) " " " "see below (*)" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" 10 Calcium regulating hormones, PTH, vitd, calcitonin a) "PTH " " " " "see below (*)" b) "vitd " " " " "see below (*)" c) "calcitonin " " " " "see below (*)" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" 11 Thyroid regulating hormones, T3-T4, TH, TRH " a) "T3-T4 " " " "see below (*)" " b) "TH " " " "see below (*)" " c) "TRH " " " "see below (*)" (*) xpand story line for each of these hormones following an order such as: origin, stimuli, biosynthesis, release, target, action mechanism, effect, integration, others" " e.g. sentences from lectures What is the endocrine system! releases chemicals into blood for distribution throughout the body. " releases hormones altering metabolism of many tissues / organs simultaneously. " produces effects that can last for hours, days, and even longer. " control ongoing metabolic processes. " many endocrine tissues have non-endocrine functions." complex endocrine responses usually involves hormones from the hypothalamus." Berthold showed that CC with testis transplant displayed male traits (comb & behavior). " What is a hormone! secreted to blood for transport to distant targets. " exerting its effect at very low concentrations. " related to a verb meaning "to excite or arouse." " whose meaning is continually being challenged. " a tropic hormone is one whose function is to stimulate another hormone secretion." some are aminoacid derivatives, others are peptides/proteins, and other are lipids." some have sub-units (LH, FH, TH, HCG, PMG)." their targets have specific receptors (high affinity / low capacity)." hypophysiotropic hormones are neurohormones controlling AP function." which endocrine organ produce which hormone in response to which main stimulus.! which is the main effect of each hormone and which is its main negative feedback control." 28

29 e.g. sentences from lectures What are endocrine actions and endocrine disruptors! hormones control of enzymatic reaction rates " hormones control molecule transport across membranes hormones control gene expression and protein synthesis" receptors altered in quantity when low or high amount of its hormone is present" water soluble hormones bind membrane receptors and affect 2 nd messengers and signaling cascades" liposoluble hormones bind transcription factors and affect protein synthesis" endocrine disruptors are environmental chemicals affecting the endocrine system." some endocrine disruptors are in sewage ( from contraceptives and dioxins from paper products)." Which are structures and control elements in the endocrine system! membranes are phospholipids bilayers (tails inside) interspersed with proteins." a portal system like the one from gut to liver links the hypothalamus with the AP." a steady state is maintained by homeostatic (eg. Insulin and glycemia)." ligands are chemicals that bind to a receptor." downregulation, expression of fewer cell surface receptors, as part of a -FB mechanism." up/down regulation is due to alterations in the rate of receptor turnover." permisivness, interaction through which one hormone "allows" another hormone to be effective. "" second messengers are intracellular signals elicited by hormones / neurotransmitters." G proteins link the first and second messenger in signal transduction." signal transduction chains (Gs,Gi,AC,cAMP,PKA); (Gq,PLC,DAG,PK,IP3,Ca,calmodulin,CK)." most widely found 2nd messenger is camp." e.g. sentences from lectures What are steroids and thyroid hormones! steroids are liposoluble hormones derived from cholesterol and made in the R" steroids are made / release upon demand, are not stored in the cell and have a long half life" main cholesterol and steroid structure is the cyclo-pentane-perhydro fenantrene group." T3-T4 are liposoluble hormones derived from tyrosine and made in the thyroid gland" T3-T4 secretion depends on TH and are stored covalently bound to TG in the thyroid" What are peptide and protein hormones! are watersoluble hormones made in the RR that bind membrane receptors" are initially made as inactive preprohormones, dissolve in plasma and have a short half life "!!What are endocrine pathologies! primary and secondary hyperfunctions and hypofunctions" principal pathologies related to each main hormone systems" 29

30 e.g. sentences from lectures What are steroids and thyroid hormones! steroids are liposoluble hormones derived from cholesterol and made in the R" steroids are made / release upon demand, are not stored in the cell and have a long half life" main cholesterol and steroid structure is the cyclo-pentane-perhydro fenantrene group." T3-T4 are liposoluble hormones derived from tyrosine and made in the thyroid gland" T3-T4 secretion depends on TH and are stored covalently bound to TG in the thyroid" What are peptide and protein hormones! are watersoluble hormones made in the RR that bind membrane receptors" are initially made as inactive preprohormones, dissolve in plasma and have a short half life "!!What are endocrine pathologies! primary and secondary hyperfunctions and hypofunctions" principal pathologies related to each main hormone systems" In the first endocrinology test there were roughly questions that were repeated.! For example, 7 were based on the following 3 short sentences! (active learning! based technique):!! steroids are liposoluble hormones derived from cholesterol and made in the R." steroids are made / release upon demand, are not stored in the cell and have a long half life." main cholesterol and steroid structure is the cyclo-pentane-perhydro fenantrene group." e.g. questions from test #1 teroids are synthesized in the! a "rough endoplasmic reticulum. " b "smooth endoplasmic reticulum. " c "Golgi apparatus, most of the times. " d "mitochondria, predominatly for export. " e "nucleus, where steroids receptors are." teroids are defined as hormones that are " a "always defined as lipophilic or water insoluble." b "always defined as hydrophobic or liposoluble." c "always derived from cholesterol or from acetate." d "secreted by cortex but not by adrenal medulla." e "all of the above options are correct." teroids, liposoluble, cholesterol, R. Made/release upon demand, long half-life. Cyclo pentane perhydro fenantrene group. teroids differ from peptides since steroids" a "synthesis site is distinct from their release site." b "are not stored, but are released upon synthesis." c "are synthesized ubiquitously (all over the body). " d "don't have a specific receptor protein to bind to." e "none of the above options is correct." The preovulatory blood 2 rise may reflect " a "high 2 secretion by all steroidogenic tissues." b "high rates of synthesis of 2 by the ovary. " c "high cholesterol ingestion leading to higher plasma levels of all steroid hormones." d "decreased rates of degradation of estrogen." e "decreased rates of excretion of estrogens." 30

31 e.g. questions from test #1 The following have a cyclopentane perhydrophenanthrene nucleus, XCPT" a "the hormone whose acronym is TH." b "the hormone whose acronym is P4." c "the hormone whose acronym is T." d "the hormone whose acronym is 2." e "the hormone whose acronym is DHA." Testosterone, cortisol and estrogen are " a "all examples of chemical enzymes" b "examples of chemical glycoproteins" c "examples of chemical phospholipids" d "examples of transcription factors" e!none of the above options is correct" teroids, liposoluble, cholesterol, R. Made/release upon demand, long half-life. Cyclo pentane perhydro fenantrene group. A steroid found in the blood, made in the ovary and acting on the pituitary, was" a "made in the R of a cell cytoplasm." b "made in the nucleous of a target cell." c "made in the RR of a cell cytoplasm." d "sorted by the Golgi apparatus of a cell." e "bound to cellular lysosomes in a cell." Review #2 16 Review using OPAL figures Review using class web PDF Review using test #1 Preview of test #2 31

32 Test #2 ndocrinology, test#2, JP Advis.! Name (also fill bubbles in scantron)! tudent ID (also fill bubbles in scantron)! Web ID (also write in scantron upper/right)! eat (also write in scantron upper/right)! Note: all the above info also goes in the scantron,! with the webid and the seat in the upper right corner.! FOR ALL QUTION LCT TH! BT ANWR FROM TH OPTION GIVN! 32