Transcript Karbohidrat Metabolizması

GLUCAGON AND ADRENALINE ACTION REGULATION OF METABOLISM
Hormone
Glucagon
Adrenaline
Receptor subtype
G
glucagon
adrenergic
2nd
messenger
cAMP
Metabolic response
PKA

Gs
cAMP
PKA
2
Gi
cAMP
PKA
inactive
1
Gq
IP3
DAG
Ca2+
PKC
Regulation of
enzyme activity
FUEL MOBILISATION
Overview of fuel mobilisation in different tissues
LIVER
BRAIN
glucose
glucose
glucose
gluconeogenesis
glycerol
AA
CO2 + H2O
AA
glycogenolysis
glycogen
FA + glycerol
glycogen
FA
lipolysis
triglyceride
protein
CO2 + H2O
MUSCLE
ADIPOSE TISSUE
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
Regulation of glycogenolysis by glucagon and adrenaline
(remember also allosteric regulation – see Prof. Denton's lectures)
glycogen
PHOSPHORYLASE
-
+
P
P
glucagon
adrenaline (β)
PKA
GLYCOGEN
SYNTHASE
glucose-1-P
PKA
glucagon
adrenaline (β)
PKA acts on phosphorylase kinase
PKA
phosphorylase
kinase b
phosphorylase b
phosphorylase
kinase a P
phosphorylase a P
glycogen n
glycogen
n-1
+
glucose 1-P
glucose-6-P
glucose
(liver)
glycolysis
& TCA cycle
(muscle)
PKA directly phosphorylates glycogen synthase
PKA
glycogen
synthase a
glycogen
synthase b P
(inactive)
glycogen
n-1
+
UDP glucose
glucose 1-P
glycogen n
Protein phosphatase-1 is inactivated by an inhibitor protein
PKA
ATP
PKA
ADP
phosphorylase
kinase b
glycogen
synthase a
phosphorylase
kinase a P
glycogen
synthase b P
(inactive)
Pi
PP-1
PP-1
-
-
Inhibitor protein P
Inhibitor protein P
PKA
Inhibitor protein
AMPLIFICATION occurs by simultaneous activation of
glycogen breakdown and inhibition of glycogen synthesis
1 adrenergic receptors
Ca2+
Activation of phosphorylase kinase by Ca2+ and PKA
subunit is
catalytic



PKA
P
P
subunit is calmodulin
P
4Ca2+

phosphorylase
kinase
P

Ca2+
Ca2+
Ca2+
Ca2+
4Ca2+
P
1500
30-fold increase in
phosphorylase kinase activity
1000
% activity
500
10-7 10-6 10-5 10-4
[Ca2+] M
Glucagon stimulates gluconeogenesis in liver
- role of F2,6,P2
PC and PEPCK subject to
long-term regulation
amino acids,
lactate
pyruvate
glycerol
PKA
PK
PC
oxaloacetate
Glucagon
PEPCK
phosphoenol pyruvate
F2,6P2
F1,6P
FBPase1
+
PFK-1
F6P
+
F2,6P2
PKA
FBPase2
F2,6P2
PFK-2
glucose 6-P
glucose-6
phosphatase
glucose
F6P
Net result is to
decrease F2,6,P2
Adrenaline stimulates glycolysis in muscle (heart)
TCA
cycle
pyruvate
Heart has a different isoform of
FBPase2/PFK2
phosphoenol pyruvate
FBPase2
F2,6P2
F1,6P
FBPase1
+
PFK-1
F6P
glucose 6-P
Gycogen
F2,6P2
PKA
F2,6P2
+
F6P
PFK-2
Regulation of triglyceride breakdown
(lipolysis)
PKA
triglyceride
lipase
Triglyceride
triglyceride
lipase P
fatty acids + glycerol
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)