Regulation of Glycogenolysis Figure modified from Yan A et al 2016 In J Biol Sci 121215441554 and Servier Medical Art GDP cAMP Protein Kinase A PKA PKA Regulation of ID: 921106
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Slide1
Glycogen Biosynthesis and Metabolism – Part 5
Regulation of
Glycogenolysis
Slide2Figure modified from
Yan, A., et al (2016) In J
Biol
Sci
12(12):1544-1554
and
Servier Medical Art
GDP
cAMP
Protein Kinase A
(PKA)
PKA
Regulation of
Glycogenolysis
in Liver Cells
Glycolysis
Glycogenesis
Glycogenolysis
Slide3Figure modified from
Yan, A., et al (2016) In J
Biol
Sci
12(12):1544-1554
and
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
GDP
cAMP
PKA
Glucagon Signaling in Liver Cells
Phosphorylase
Kinase
Phosphorylase
Kinase
P
P
P
P
Glycogen Phosphorylase
Glycogen Phosphorylase
(more active)
P
P
Slide4Phosphorylase Kinase
Is a Tetramer that is regulated by phosphorylation by PKA and by binding with Ca
2+
Calcium can be released in cellular targets due to nerve impulses, muscle contraction, or through hormone signaling.
Maximal activity is achieved when both phosphorylation and Ca
2+ are present
Slide5Phosphorylase Kinase
P
P
P
P
Ca
2+
Ca
2+
Ca
2+
Ca
2+
ADP
ATP
ADP
ATP
ADP
ATP
Ca
2+
Ca
2+
Ca
2+
Inactive
Partially Active
Partially Active
Ca
2+
Ca
2+
Ca
2+
Ca
2+
P
P
P
P
Fully Active
Slide6Regulation of Glycogenolysis
is different in Liver and Skeletal Muscle (other tissues)
Image modified from
Ascherer730
Activated by different hormones
Liver activated by both Glucagon and Epinephrine
Skeletal Muscle activated by Epinephrine
Have different Isozymes of Glycogen Phosphorylase
Slide7Epinephrine
Also called Adrenaline
Secreted during flight or fight response or during strenuous exercise
Pleiotropic Physiological Responses
Increases glycogenolysis in liver and skeletal muscle
Increases lipidolysis in adipose tissueRelaxation of smooth muscles in lungs and respiratory track
Increase in cardiac contractilityConstrict blood flow to the skinContract smooth muscles of skin (hair raises/goosebumps)
Slide8Comparison of Glucagon and Epinephrine Signaling in Liver and Skeletal Muscle
Glucagon
Epinephrine
Epinephrine Receptor
(G-protein coupled receptor)
Glucagon Receptor
(G-protein coupled receptor)
G-protein
Adenylate Cyclase
PKA
Pleiotropic Effects
Slide9Regulation of Glycogenolysis
is different in Liver and Skeletal Muscle (other tissues)
Image modified from
Ascherer730
Activated by different hormones
Liver activated by both Glucagon and Epinephrine
Skeletal Muscle activated by Epinephrine
Have different Isozymes of Glycogen Phosphorylase that are regulated by a combination of:
Allosteric Effectors
Reversible Phosphorylation
Slide10Glycogen Phosphorylase (Both Isozymes)
Image modified from
Ascherer730
Glycogen Phosphorylase exists in two major conformations:
a-form (phosphorylated)
b-form (dephosphorylated)
The state of the protein can also be either Relaxed (more flexible) or Tense (less flexible).
The Relaxed (R-state) is active and is favored by the a-form The Tense (T-state) is inactive and is favored by the b-form
Slide11Glycogen Phosphorylase Enzymes
Image modified from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
P
P
P
P
b-form
a-form
R-state
(active)
T-state
(inactive)
Slide12Glycogen Phosphorylase
Image modified from
Ascherer730
ISOZYMES are also regulated by Allosteric Effectors
Liver
Glucose is a negative regulator
Skeletal Muscle
Glucose 6-phosphate is a negative regulatorATP is a negative regulator
AMP is a positive regulator
Slide13Liver Glycogen Phosphorylase
P
P
P
P
a-form
R-state
(active)
T-state
(inactive)
Image modified from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
Glucose
Glucose blocks the activity of Liver Glycogen Phosphorylase, even in the presence of
phosphyrlation
!
Slide14Glycogen Phosphorylase
Image modified from
Ascherer730
ISOZYMES are also regulated by Allosteric Effectors
Liver
Glucose is a negative regulator
Skeletal Muscle
Glucose 6-phosphate is a negative regulatorATP is a negative regulator
AMP is a positive regulator
Slide15Glycogen Phosphorylase
Image modified from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
P
P
P
P
b-form
a-form
R-state
(active)
T-state
(inactive)
P
Glucose
6-phosphate
P
P
P
P
P
P
P
P
NEGATIVE
REGULATOR
Slide16Glycogen Phosphorylase
Image modified from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
P
P
P
P
b-form
a-form
R-state
(active)
T-state
(inactive)
ATP
NEGATIVE
REGULATOR
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
Slide17Glycogen Phosphorylase
Image modified from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
P
P
P
P
b-form
a-form
R-state
(active)
T-state
(inactive)
AMP
POSITIVE
REGULATOR
P
P
P
P
P
P
P
P
P
Slide18McArdle’s Disease
Image from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919
Slide19Summary of Glucose Metabolism in Muscle
Image from
Llavero
, F., et al (2019) Int. J. Mol. Sci. 20(23):5919