Hormones of fasting and stress 1

Learning objectives:
1. Fuel mobilisation in starvation by glucagon, adrenalin and glucocorticoids
2. Glucagon signalling: the glucagon receptor as a member of the membrane spanning group
3. Role of G proteins in signal transduction
4. cAMP as a second messenger
5. Adrenergic receptors
6. IP3 and calcium as second messengers
7. Hormones of the pancreas: insulin and glucagon synthesis and secretion - regulation of blood levels
Endocrine system
1. pancreas - insulin and glucagon
  1. main hormones that regulate metabolism
2. adrenal glands - adrenaline and glucocorticoids
3. Glands = pineal, pituitary, thyroid, parathyroid (head) , pancreas, adrenal gland, ovaries/testes (abdominal)
4. Hormones released into blood stream and act on a different cell (hemocrine)
  1. Hormone clearance by liver and kidneys:
    1. half-life in plasma:
      1. Amine 2-3 mins
      2. Peptides 4-40 mins
      3. Steroids 4-120 mins
5. NET EFFECT of hormones acting on metabolism
  1. levels of hormones vary - circulate together in different amount. Specificity brought by distribution of RECEPTORS on target tissues
Hormone action
1. Hormone -> receptor -> signalling pathway -> target enzyme -> cell response e.g. change in metabolism, contraction, secretion
2. hormones act by binding to receptors; target proteins where hormones have to bind to elicit an effect
3. Hormone receptors - 3 classes:
  1. G-protein coupled receptors
    1. receptor external - e.g. adrenaline, glucagon - 2nd messengers elicit effect within cell
  2. Peptide hormone receptors
    1. autocatalytic activity - kinase cascades
      1. e.g. insulin, growth hormones
  3. Steroid hormone receptors
    1. receptor internal -e.g.cortisol
4. Some receptors open into ion channels e.g. neurotransmitters e.g. acetyl choline on Na+ entry
Metabolic regulation and integration
1. Insulin and glucagon - respond to blood glucose
2. Adrenaline, glucocorticoids e.g. cortisol (steroids) - STRESS hormones
  1. longer term response - fight or flight
3. why hormones needed to regulate metabolism?
  1. rapid, coordinated response of metabolism in dif. tissues to change in body demands e.g. FASTING, feeding, EXERCISE, rest, STRESS (fight/flight response)
  2. allow coordinated regulation of metabolism between different organisms
    1. abnormal hormonal action - disease - e.g. diabetes, obesity
  3. metabolism regulated by change in activity of enzymes
    1. INTRINSIC
    2. EXTRINSIC
      1. regulation of enzyme activity by hormones e.g. allosteric feedback inhibition
        short term - COVALENT modification
        minutes/seconds
        e.g. Phosphatase -> kinase
        reversible phosphorylation of enzymes
        long term - change in enzyme levels by regulating GENE TRANSCRIPTION
Regulation of glucose homeostasis
1. 4.5 -5.0Mm. 3.5mM fasting. 6.5mM fed.
2. HIGH glucose = insulin release - glucose removal (into muscle and adipose tissue)
3. LOW glucose = glucagon release - glucose synthesis (by liver)
4. Adrenaline + cortisol - low blood glucose = stress
5. Hormone action
  1. GLUCAGON = secreted when glc low. Signals fasting state. Stimulates glucose release by liver.
  2. ADRENALINE - secreted in response to stressfull stimuli: fear (fight/flight), low blood glucose
    1. stimulates fuel mobilisation - muscle, adipose tissue, liver
  3. GLUCOCORTICOIDS - secreted in response to STRESS - long term effects (enzyme synthesis)
    1. morning and night
  4. INSULIN - response to high blood glucose. Signals 'fed' state. Stimulated glucose uptake by adipose tissue and muscle.
6. Toxic glucose
  1. HYPOglyceamia - no fuel for brain
    1. (mild) - sweating, nausea, palpitations. (severe) - drowsiness, unsteady, confusion, appear drunk. coma, death
  2. HYPERglyceamia
    1. osmotic diuresis - loss of fluid and electrolytes - excessive thirst
    2. protein glycosylation - vascular disease - cataracts
    3. kidney disfunction - hypertension, heart disease
      1. glycosylation - poor circulation - high blood pressure
7. Insulin increases and peaks with blood sugar after a meal. Glucagon decreases from a higher level
  1. Insulin/glucagon ratio = at night, determines net effect
Measurement of hormone levels
1. 1. ELISA - enzyme linked immunosorbent assay
  1. used to detect/quantify of hormones and drugs
    1. Uses - measurement/detection of hormone levels (pregnancy, thyroid hormone), illegal drugs, viral infections (HIV, hepatitus B)
      1. antibody to hormone of interest immobilised in plastic well
        incubate with blood/urine sample - hormone will bind to antibody
        incubate with 2nd (animal) antibody attached to an enzyme
        wash unbound 2nd antibodies, incubate with enzyme-substrate. Coloured product can be quantified - using sprectrometer and compare w/ standard curve prepared using purified hormone
      2. pregnancy test - humans and horses!
2. 2. Radioimmunoassays
3. commonly used to detect and quantify hormones and drugs
4. Assays v. sensitive as circulating hormone levels low
Glucagon and Adrenaline action
1. Glucagon/adrenaline -> specific receptor -> signalling pathway -> 2nd messengers = cAMP, IP, Ca2+ = activation of protein kinases
  1. change in metabolism = glycogenolysis (liver,muscle) lipolysis (adipose tissue), gluconeogenesis (liver)
    1. control of enzyme activity by reversible phosphorylation
2. Receptors and subtypes
  1. Glucagon - receptor of glucagon in liver
  2. Adrenaline (+noradrenaline) - ADRENERGIC receptor - B1, B2, a1, a2 SUBTYPES, adipose tissue, heart, liver, muscle (skeletal,smooth), islet cells of pancreas
  3. Receptor common features
    1. 7-transmembrane domain receptors (7-TMDR) 'serpentine'
    2. G-protein-coupled receptors (GTP, GDP)
      1. guanosine triphosphate
      2. guanosine diphosphate
G-protein coupling, Glucagon
1. G protein - HETEROTRIMERIC, differ in Ga subunit, glucagon coupled to Ga - stimulates adenylate cyclase
  1. G.p complex attached to hydrophobic side of membrane like 'slidy handle'
2. Binding of glucagon causes conformational change of protein on intracellular side of protein - causing G protein to swap GDP for GTP
  1. GDP dissociates from a subunit
    1. a subunit hydrolyses GTP -> GDP using adenylate cyclase and cAMP
      Annotations:
      - cAMP = cyclic AMP
      1. GDP reattaches to start process again.
        GDP = inactivated
        GTP = activated
        GTPase regulates activity of Ga subunit
cAMP activates protein kinase A
1. protein kinase A, 2xregulatory, 2x catalytic molecules
  1. cAMP inhibits regulatory R2 so protein kinase just catalytic, C2
    1. PKA only acts on SERINES with CONSENSUS sequence
      1. surrounded by basic amino acids
2. caffeine inhibits cAMP breakdown
  1. Adenylate cyclase broken down to cAMP which breaks down into 5'AMP
Adrenergic receptors
1. adrenaline and noradrenaline
2. 3 major subtypes - a1, a2, B
  1. B-adrenergic receptors
    1. adrenaline stimulates/activates G-p complex
      1. beta and gamma units left behind, GDP (converted to GTP) and alpha unit join to adenylate cyclase and synthesise ATP from GDP conversion
        cAMP -> PKA -> phosphorylates enzyme
  2. a2 adrenergic receptors
    1. bind adrenaline and noradrenaline
      1. Gai (inhibitory)
        net reult of a2 stimulation by adrenaline = reduction in cAMP
        important in regulating insulin secretion
        Adenylate cyclase inhibited so cAMP formation from ATP is depressed
    2. a1 adrenergic receptors
      1. GTP and a1 bind to phospholipase C (once GDP part -> GTP)
        PIP2 of PLC produces IP3 and DAG
        inositol triphosphate and diacylglycerol - important second messengers
        Annotations:
        IP3 controls Ca2+ in the cell and DAG activates protein kinase - activates proteins inside the cell via phosphorylation
3. Removal/recycling of IP3 and DAG - switching off secondary messengers
  1. PIP2 forms:
    1. IP3
      1. broken down - INOSTIOL
    2. DAG
      1. broken down - CDP-DG
      2. reforms substrate
Adrenaline a1 receptor signalling - actions of IP3 and DAG
1. Adrenaline binds to a1 receptor, activation stimulates PLC to catalyse PIP2 breakdown
  1. DAG formed phosphorylates/activates PKC - regulating proteins - doesn't effect metabolism much
  2. IP3 second messenger opens IP3-gated calcium channel
    1. calcium normally kept inside ENDOPLASMIC RETICULUM - so to regulate concentration
    2. calcium transported into cytosol from endoplasmic reticulum
  3. Ca2+ - activation of Ca2+ binding proteins e.g. TROPONIN, CALMODULIN
    1. ALTERATION OF ENZYME ACTIVITY
      1. binding induces positive charge - changing conformation
    2. MUSCLE CONTRACTION
2. IP3 increases calcium levels indirectly within the cell
  1. 1-2mM Ca2+ in blood. 0.1mM Ca2+ in cells -> increases to 1-10mM w/adrenaline!

Media attachments

Adrenaline A1 Receptor Signalling, Actions Of Ip3 And Dag (image/jpeg)

Next up

Hormones of fasting and stress 1

Description

Resource summary

Media attachments

Similar

	Created by Florence Papworth over 7 years ago