Glycogen, TCA Cycle and Mitochondria (Lecture 8) Flashcards
explain how the insulin (tyrosine kinase receptor) functions
when insulin bind s to the tyrosine kinase receptor will autophosphorylate on the tyrosine residues
insulin promotes glycogen synthesis by supporting the activation of protein kinase (due to the Pi-Tyr residues).
the protein kinase will then inactivate glycogen synthase kinase. This relieves glycogen synthase of its repressor, since glycogen synthase kinase functions to phosphorylate glycogen synthase, thus inhibiting the synthesis process
what happens when insulin increases?
increase in insulin dependent kinase activity
increase conversion of ATP to ADP
generation of 1 state glycogen-Gm-PP1c complex
increased synthesis of glycogen
explain the G-alpha S coupled receptors
epinephrin in the muscle or glucagon in the liver will bind to the G-alpha S receptor
upon ligand binding to the receptor, this causes the G-alpha subunit to switch from GDP bound to GTP bound
the GTP bound G-alpha subunit will dissociate form the beta-gamma subunits of the receptor due to a conformational change
GTP-bound G-alpha will in turn activate adenylate cyclase to produce cAMP with an ATP molecule
cAMP will activate PKA
active PKA will triggers glycogen breakdown
explain the G-alpha Q coupled receptors
binding of a ligand to the G-alpha Q receptor will activate phospholipase C, which hydrolyses PIP2 to I3 and DAG
IP3 stimulates the release of calcium in the ER, thus activating processes via calmodulin receptors
DAG activates protein kinase C which modulates various cellular princesses such as inhibiting glycogen synthase
where do hormones act for hormonal control of glycogen?
the G-alpha S receptor produces a cAMP as a signalling molecule when stimulates by the insulin hormone. this stimulation go the G-alpha S receptor will activate PKA
also, insulin will activate glycogen synthase kinase (GSK3-B) to promote glycogen synthesis
an increase in calcium will bind to the delta subunit of phsophoryalse kinase A, which is initiated form G-alpha Q
hormones can also act of PP1c
physiological regulation in muscle
during a muscle contraction, an AP will propagate a signal to the sacrolemma and down the T tubules to generate Ca2+
this generates an influx of CA2+ in the muscles
due to this influx of calcium, an alpha adrenergic receptor is not needed to acquire the calcium
how is glycogen broken down in the muscle?
this occurs in conditions of stress/ muscle contraction
epinephrine released form the adrenal gland will bind to the muscle’s beta adrenergic receptor
the ligand receptor binding will increase the amount of cAMP
muscle contraction will increase the calcium in the cell
these two second messengers will activate PKA
the activation of PKA will inhibit glycogen synthase via phosphorylation, will activate phosphorylase kinase and activate the PP1c inhibitor, thus inhibiting PP1c
Phosphorylase kinase will activate glycogen phosphorylase to break down glycogen and it will also inhibit glycogen synthase to inhibit glycogen synthesis
this will cause the dissociation of PP1c from the Gm subunit, thus allowing PP1c to bind to its active inhibitor.
glycogen causes glycogen breakdown to produce more ATP and in turn more energy
explain glycogen synthesis in muscle:
high glucose initiates a high release of insulin
increased insulin will stimulate glucose uptake via GLUT4 in the muscle cell and activate insulin stimulated protein kinase
insulin stimulated PK will activate PP1c via the association with Gm
active PP1c will dephosphorylate glycogen synthase, thus rendering it active and capable of synthesizing glycogen
active PP1c will inhibit glycogen phosphorylase via dephosphorylation
active PP1c will also inhibit phosphorylase kinase, thus preventing this enzyme from activating glycogen phosphorylase
high G6P activates glycogen synthase
glycogen synthesis stimulated
glycogen synthesis in the liver (3 methods)
this occurs in the fed state, thus promoting glucose storage via glycogen
Insulin will inhibit GASK3-B
this releases glycogen synthase inhibition, thus activating glycogen synthesis
glucose taken up by the GLUT2 receptor will enter the liver cell and inactivate glycogen phosphorylase
G6P will also inhibit glycogen phosphorylase and it will activate glycogen synthase
the increase in insulin take-up by the insulin receptor will activate PP1c.
active PP1c will dephosphorylate glycogen synthase, which releases the inhibition off glycogen synthase (ACTIVE)
active PP1c will also inactivate glycogen synthase
active PP1c will also inactivate phosphorylase kinase, thus preventing the the inhibitions of glycogen synthase
glycogen breakdown in the liver (stress)
epinephrin released by the adrenal gland will activate the beta adrenergic receptor
the germination of cAMP will activate PKA
- activates phosphorylase kinase
- inhibits glycogen synthase
- activates PP1c inhibitor, thus inhibiting PP1c
stimulation of teh alpha adrenergic receptor wi; activate PLC
PLC will generate DAG nad IP3
IP3 increases calcium concentration in the cell, which stimulates the phosphorylase kinase, which activates glycogen phosphorylase to promote glycogen degradation
DAG activates PKC, which inhibits glucose synthase
glycogen breakdown in liver (low blood glucose)
in circumstances of fasting
glucagon is released by the pancreas
glucagon binds to its receptor to generate cAMP and activate PKA
PKA:
- activates phosphorylase kinase
- inhibits glycogen synthase
- activates PP1c inhibitor, thus inhibiting PP1c
glycogen degradation
glucose is released into the blood via GLUT2
von Gierke’s Disease
deficiency in the glucose-6-phosphatase enzyme that converts G6P into glucose and Pi
G6P is a downstream mobilizer of glycogen
G6P would accumulate, and since it cant be hydrolyzed, it will allosterically inhibit glycogen phosphatase, thus impairing glycogen breakdown
this results win the inability to increase blood glucose in response to glucagon/epinephrine
symptoms include:
liver enlargement (build up of glycogen)
hypoglycemias (cant release glucose into blood)
failure to thrive
can be fixed by inhibiting the uptake of glucose in the liver via surgical transposition of the portal vein, which reroute to feed glucose to other tissues
McArdle’s Disease
enzyme deficiency in glycogen phosphorylase in the MUSCLE
catalyzes the glycogen breakdown to G1P
glycogen breakdown is impaired, reduced fuel of glycogen to keep up with metabolic demands
symptoms include painful cramps during exercise because ADP levels are elevated during light exercise
note that these high levels occur because ATP cant be produced efficiently (since glycogen cant be mobilized and form glucose)
Her’s Disease
enzyme deficiency in glycogen phosphorylase in the LIVER
catalyzes the glycogen breakdown to G1P
glycogen breakdown is impaired
symptoms include hypoglycaemia due to the fact that glycogen phosphorylase cannot respond to the need for glucose in the liver when signalled by glucagon
cori cycle
maintains energy during exercise, since lactate is released by the liver to create glucose
maintains glycolytic flux by removing NADH. this is done by reducing pyruvate to lactate. this then regenerates NAD+ to feed glycolysis
a build up of lactate isn’t favourable, so lactate is released into the blood to regenerate glucose via gluconeogenesis I the liver
