Glucagon Adrenaline

1. 2nd messenger Gα Hormone Receptor subtype glucagon adrenergic PKA Glucagon Adrenaline Metabolic response β α2 α1 Gs PKA Regulation of enzyme activity cAMP PKA inactive Gi Gq IP3 DAG Ca2+ PKC FUEL MOBILISATION cAMP cAMP GLUCAGON AND ADRENALINE ACTION - REGULATION OF METABOLISM

2. Overview of fuel mobilisation in different tissues LIVER BRAIN glycogenolysis glucose glucose glucose glycogen gluconeogenesis glycerol CO2 + H2O AA FA + glycerol glycogen AA FA lipolysis triglyceride protein CO2 + H2O ADIPOSE TISSUE MUSCLE FA – fatty acids AA – amino acids Glucagon acts on liver to maintain blood glucose levels (gluconeogenesis and glycogenolysis) Adrenaline acts on: muscle – glycogenolysis liver - glycogenolysis adipose – lipolysis tissue

3. - P glucagon adrenaline (β) PKA glucagon adrenaline (β) PKA + P Regulation of glycogenolysis by glucagon and adrenaline (remember also allosteric regulation – see Prof. Denton's lectures) glycogen GLYCOGEN SYNTHASE PHOSPHORYLASE glucose-1-P

4. PKA phosphorylase kinase b phosphorylase kinase a phosphorylase b phosphorylase a glucose-6-P + glucose 1-P glucose (liver) glycolysis & TCA cycle (muscle) glycogen glycogen n-1 n P P PKA acts on phosphorylase kinase

5. - glycogen glycogen n n-1 + UDP glucose glucose 1-P P PKA directly phosphorylates glycogen synthase PKA glycogen synthase a glycogen synthase b (inactive)

6. PKA glycogen synthase a glycogen synthase b phosphorylase kinase a (inactive) PP-1 phosphorylase kinase b - - Inhibitor protein Inhibitor protein PKA Inhibitor protein P P P P Protein phosphatase-1 is inactivated by an inhibitor protein PKA ATP ADP Pi PP-1 AMPLIFICATION occurs by simultaneous activation of glycogen breakdown and inhibition of glycogen synthesis

7. 1adrenergic receptors Ca2+ Activation of phosphorylase kinase by Ca2+ and PKA P P P P α γ subunit is catalytic γ β δ PKA 4Ca2+ γ 4Ca2+ phosphorylase kinase δ subunit is calmodulin Ca2+ Ca2+ Ca2+ Ca2+ P 1500 30-fold increase in phosphorylase kinase activity 1000 % activity 500 10-6 10-5 10-4 10-7 [Ca2+] M

8. Glucagon F2,6P2 FBPase2 F2,6P2 + + PKA F1,6P F2,6P2 F6P FBPase1 PFK-1 PFK-2 F6P glucose 6-P glucose-6 phosphatase Net result is to decrease F2,6,P2 glucose Glucagon stimulates gluconeogenesis in liver - role of F2,6,P2 PC and PEPCK subject to long-term regulation amino acids, lactate pyruvate PC glycerol oxaloacetate PKA PK PEPCK phosphoenol pyruvate

9. TCA cycle Heart has a different isoform of FBPase2/PFK2 pyruvate FBPase2 PKA F2,6P2 F6P phosphoenol pyruvate + PFK-2 F2,6P2 + F2,6P2 F1,6P FBPase1 PFK-1 F6P glucose 6-P Gycogen Adrenaline stimulates glycolysis in muscle (heart)

10. PKA Triglyceride triglyceride lipase triglyceride lipase P fatty acids + glycerol Regulation of triglyceride breakdown (lipolysis)

11. “mobilisation of energy resources and shunting to where they are most needed to prepare the body for sudden action” • increase heart rate and force • Smooth muscle relaxation (bronchi and skeletal muscle) • Smooth muscle contraction in peripheral organs (e.g. skin/kidney) • Smooth muscle relaxation (gut) Net effect of adrenaline……….. (Fight-or-flight response) • glycogen breakdown • triglyceride breakdown • stimulate glucagon release • inhibit insulin release