The Contribution of Cell Signalling Towards Metabolic Functions-Richard Flashcards
Catabolism
(eg. Stimulation of Glycogen Breakdown)
Signalled by:
Glucagon (liver)
Adrenaline (muscle)
Signal Transduction via 2nd messengers [cAMP].
Anabolism
(eg. Stimulation of Glycogen Synthesis)
Signalled by: Insulin
Signal Transduction via Receptor Protein Kinase [InsR]
Catabolism: Glucagon
*Polypeptide hormone (29 AAs) secreted by alpha cells of pancreas in response to decrease [glucose]blood
CATABOLISM: Glucagon continued
t½ ~ many minutes in bloodstream (endocrine factor). Interacts with GPCR receptor on PM of target cells (eg. in liver).
Signalling Cascade initiated by release of ‘2nd messenger’ cAMP (triggered by G-protein adjacent to GPCR); leads to:
eg. phosphorylation of substrate proteins, catalysed by cytoplasmic enzyme, cAMP-dependent protein kinase: Protein Kinase A.
Summary of catabolic glucagon mechanism
Phosphorylation of Glycogen Phosphorylase & stimulation of breakdown of glycogen for energy.
Phosphorylation of Hormone-Sensitive Lipase & stimulation of breakdown of triglyceride for energy
Also, other effects which impact on suppression of fatty acid synthesis, glycogen synthesis, etc
What is the net effect of catabolism?
ENERGY USAGE; “Signals the ‘hungry’ state”
What is Cyclic AMP (cAMP)?
‘2nd messenger’: nucleotide derivative produced from ATP by Adenyl cyclase in response to Glucagon interacting with nearby receptor/G-protein:
*An activator of Protein Kinase
Sutherland analogy of cAMP:
“We may visualize the hormone as a messenger which arrives at the door of the house and rings the bell. The messenger is not allowed to enter the house. Instead the message is given to a servant, cyclic AMP, which then carries it to the interior of the house.” Sutherland, 1971
What happens regarding Phosphodiesterases & cAMP Spikes
Increases in concn of 2nd messengers must be reversed by rapid decreases when the external stimulus is removed (cAMP spikes: ~200nM <-> ~0.1mM).
cAMP is degraded by Phosphodiesterases to 5’AMP
If [cAMP] rises above ~0.1mM –Within <0.5sec of its synthesis
What are the many targets for cAMP:
cAMP directly interacts with effector molecules including cyclic nucleotide-gated ion channels, cAMP-regulated G protein exchange factors, and cAMP-dependent protein kinase (PKA).
What is Protein Kinase A (“PKA”)?
cAMP-activated ubiquitous Ser/Thr Kinase
Importance of PKA:
25% of PKA in active form basally; increase cAMP -> 50-100% of PKA in active form
PKA phosphorylates any exposed Ser/Thr found within the following consensus sequence on a substrate polypeptide:
ArgArgXser/ThrX
Role of PKA:
A phosphate group [green] is transferred from ATP to an OH group of the substrate polypeptide [orange].
This affects the 2o & 3o structure of the substrate polypeptide (ie. how it folds up), & therefore its function.
Anabolism: Insulin
~6 KDa polypeptide (51 AAs)
secreted by ß cells of pancreas,
in response to high [glucose]blood
Signals the well-fed state: stimulates glucose uptake into cells, & storage of fuels/energy; also synthesis of protein within cells.
t½ ~ many minutes in the bloodstream – an endocrine factor.
Interacts with Receptor Tyr Kinase (Insulin Receptor [IR]) on surface of Target Cells; exerts powerful anabolic effects throughout body.
IR responds to ligand binding by phosphorylating substrate proteins near PM, which in turn phosphorylate proteins deeper within cytoplasm:
Phosphorylates Glycogen Synthase; stimulates glycogen synthesis (in liver and muscle)
Phosphorylates Ribosomal S6 & promotes protein synthesis.
Phosphorylates Akt & promotes entry of glucose into cells.
Phosphorylatn of enzymes involved in Fatty Acid Synthesis, etc
What is the net effect of anabolism?
Energy storage
Type-2 Diabetes & Insulin Signalling: Healthy aspect-
As we know, insulin interacts specifically with a Receptor Tyrosine Kinase (Insulin Receptor), which phosphorylates a substrate protein (Insulin Receptor Substrate [IRS]), which initiates signalling effects in many different cell types (esp. muscle, adipocytes) to exert anabolic effects.
Glucose uptake into cells/Synthesis of energy storage forms: glycogen, fat & protein.
Type-2 Diabetes & insulin signalling: unhealthy aspect-
However, poor vascularisatn of large adipose tissue deposits in obesity -> cells often exist in hypoxic conditions, & respond by inflammation.
Pro-inflammatory signals trigger HYPERphosphorylation of IRS in nearby cells, which therefore can’t take up the ‘correct’ 3D shape which IRS has when phosphorylated ‘normally’ by the Insulin Receptor.
Thus, in T2DM, the normal IRS signalling processes DON’T occur due to obesity-linked abnormal pro-inflammatory cell signalling, and so we see the symptoms of Type-2 Diabetes.
Abnormal Cell Signalling: Obesity (ie. increased energy storage as fat, especially in Visceral Adipocytes) leads to:
-increased visceral adipocyte-linked signalling
-increased circulating glucose
-Lower production of Adiponectin by adipocytes
-Higher expression of TAG-breakdown enzymes
-Lower expression of Leptin by adipocytes
Effect of increased Visceral Adipocyte-linked signalling:
↑ expressn of pro-inflammatory cytokines (eg. TNFalpha)
*Pro-inflammatory processes; disruptn of Insulin signalling (linked to abnormal phosphn of IRS)
–Muscle: disrupt Insulin’s role promoting Glucose uptake (linked to abnormal phosphn of IRS)
–Liver: disrupt Insulin’s role in inhibiting Gluco-neogenesis (linked to abnormal phosphn of IRS)
–General: Slower proteolytic breakdown of Insulin
Effect of Lower production of Adiponectin by adipocytes:
- Decreased beta-oxidation; increased plasma triglycerides
- Higher expression of TAG-breakdown enzymes
- Increased circulating Free Fatty Acids
Effect of Lower expression of Leptin by adipocytes:
Loss of leptin’s actions on brain cells -> suppress of appetite (no “satiation”)
Overall effect/symptoms of obesity:
-increased blood glucose conc.
-increased blood insulin conc.
-increased blood lipid conc.
chronic inflammation
->
- Insulin resistance
- Hyperglycaemia
- Dyslipidaemia
Hyperglycaemia:
Because ‘Insulin Signalling’ interaction is abnormal, Glucose is spurned!
High blood glucose (Hyperglycaemia) leads to excess GLYCATION of proteins, lipids etc:
Disrupted functions
Chronic inflammation
