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GLUCAGON AND ADRENALINE ACTION - REGULATION OF METABOLISM
adrenergic β α2 α1 cAMP IP3 DAG Ca2+ PKC PKA inactive Hormone Receptor subtype 2nd messenger Gα Gs Gi Gq Regulation of enzyme activity Metabolic response FUEL MOBILISATION
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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
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Regulation of glycogenolysis by glucagon and adrenaline
(remember also allosteric regulation – see Prof. Denton's lectures) glycogen GLYCOGEN SYNTHASE PHOSPHORYLASE PKA glucagon adrenaline (β) - P + PKA glucagon adrenaline (β) P glucose-1-P
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PKA acts on phosphorylase kinase
kinase b kinase a P PKA phosphorylase b phosphorylase a P glycogen n n-1 + glucose 1-P glucose-6-P glucose (liver) glycolysis & TCA cycle (muscle)
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- PKA directly phosphorylates glycogen synthase PKA glycogen
synthase a glycogen synthase b P (inactive) + UDP glucose glucose 1-P glycogen n n-1 -
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AMPLIFICATION occurs by simultaneous activation of
Protein phosphatase-1 is inactivated by an inhibitor protein PKA glycogen synthase a P synthase b PP-1 PKA (inactive) ATP ADP phosphorylase kinase b phosphorylase kinase a P Pi PP-1 Inhibitor protein P - Inhibitor protein P - Inhibitor protein PKA AMPLIFICATION occurs by simultaneous activation of glycogen breakdown and inhibition of glycogen synthesis
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phosphorylase kinase activity
Activation of phosphorylase kinase by Ca2+ and PKA 1 adrenergic receptors Ca2+ γ subunit is catalytic α β γ δ phosphorylase kinase P PKA δ subunit is calmodulin Ca2+ γ 4Ca2+ P P 1500 30-fold increase in phosphorylase kinase activity 1000 % activity 500 10-7 10-6 10-5 10-4 [Ca2+] M
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Glucagon stimulates gluconeogenesis in liver
- role of F2,6,P2 PC and PEPCK subject to long-term regulation amino acids, lactate pyruvate PC glycerol PKA + Glucagon Net result is to decrease F2,6,P2 oxaloacetate PKA PK PEPCK phosphoenol pyruvate F2,6P2 + FBPase1 PFK-1 F1,6P F6P glucose 6-P glucose glucose-6 phosphatase F2,6P F6P FBPase2 PFK-2
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Heart has a different isoform of
Adrenaline stimulates glycolysis in muscle (heart) pyruvate phosphoenol pyruvate F1,6P F6P glucose 6-P PFK-1 FBPase1 F2,6P2 + TCA cycle Gycogen PKA + F2,6P F6P FBPase2 PFK-2 Heart has a different isoform of FBPase2/PFK2
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Regulation of triglyceride breakdown
(lipolysis) Triglyceride fatty acids + glycerol triglyceride lipase P PKA
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Net effect of adrenaline……….. (Fight-or-flight response)
glycogen breakdown triglyceride breakdown stimulate glucagon release inhibit insulin release “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)
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