Signal Transduction Flashcards
What is signal tranduction
Way for signal from outside to affect function via amplification
Flow chart of tranduction
Signal —– reception —- transuction —– response
Amplification from reception to transduction
Epinephrine binds
7 transmembrane domain protein known as a G-protein coupled receptor
G-protein coupled receptor that epinephrine binds to interacts with ____ and what does it do?
Heterotrimeric G protein that has 3 subunits
Will activate another enzyme
Epinephrine signaling pathway
Epinephrine binds B adrenergic receptor…G-protein phorphorylated and loses beta and gamma subunits…GTP with alpha unit binds to adenylate cyclase…adenylate cyclase converts ATP to cyclic AMP….cyclic AMP activates protein kinase A…PKA then phosphorylates serine residues on target proteins
Adenylate cyclase rxn
ATP —- cyclic AMP
Cyclic AMP rxn
Protein Kinase A ——- activate protein Kinase A
Protein kinase A regulated by (what mechanism)
Autoinhibition
1st part of cAMP cascade termination
Epinephrine dissociates…bARK phosphorylates tail of receptor…this binds B-arrestin that blocks binding of new heterotrimeric proteins
bARK name and function
Beta-adrenergic-receptor kinase
Phosphorylates receptor using ATP to allow recruitment of B-arrestin
B-arrestin function
Blocks new heterotrimeric G-proteins from binding receptor
Second part of cAMP termination
GTP associated G-protein with adenylate cyclase undergoes hydrolysis to make GDP…beta and gamma subunits return and molecule dissociates
What happens to cyclic AMP during termination
Hydrolyzed by cyclic AMP phosphodiesterase to AMP
Cholera enzyme rxn
Catalyzes ADP-ribosylkation of G-protein alpha subunit
Cholera mechanism of disease
Internal GTPase is blocked and left in on state…overproduction of cAMP and PKA leads to membrane ion transport protein phosphorylation…loss of ions and water leads to diarrhea
Intestinal
Pertussis rxn
ADP-ribosylation of the heterotrimeric subunit (which is inhibitory)
Pertussis mechanism of disease
Blocks exchange of GTP for GDP and therefore heterotrimeric subunits with GDP remain off…adenylate cyclase, once on, is never turned off
Respiratory tract
Enzyme-linked receptors
Transduce an external signal across membrane by generating intramolecular enzymatic activity
Cytokine receptors
Receptor has NO intrinsic enzymatic activity and a second protein is activated by the binding of the cytokine or signaling agent
Cytokine receptors often activated
Jak-STAT signaling
Insulin receptor structure
Dimer with two extracellular alpha for binding pocket of insulin…each B subunit contains kinase omain
Binding of insulin results in
Cross-phosphorylation and activation of the receptor
Phosphorylated insulin receptor sites act as binding site ofor
IRS-1
IRS-1 allows binding of
PI-3K
PI-3K rxn
PIP2 —- PIP 3
PIP3 function
Activates PIP 3-dependent kinase
PIP 3-dependent kinase function
phophorylates and activates kinases such as AKT
Insulin pathway
Receptor phosphorlates IRS…IRS binds PI3K…PI3K converts PIP2 to PIP3 via phosphorylation…PIP3 activates Pip3 dependent kinase…PIP3 dependent kinase phosphorylates AKT to activate it
insulin structures
Dimer linked by 2 disulfide
Type 1/2 diabetes onset, age, body, ketoacidosis
1 - sudden, any age, thin or normal, common
2 - gradual, adults, often obese, rare
Type 1/2 diabetes autoantibodies, andogenous insulin, concordance in ID trwins, prev
1 - usually present, low or absent, 50%, less
2 - Absent, Normal increased or decreased , 90%, more prevalent
Type 1 diabetes symptoms
Polyuria Polydipsia Polyphagia Fatigue/weakness Irratability Blurred vision Increased yeast infections
Characteristics of T1DM
Hyperglycemia caused by increased gluconeogenesis and insufficient glucose absorption
Ketosis from accumulation of free fatty acids
Underlying cause of T1DM
Autoimmune disorder leads to destruction of B cells in pancreas
T2DM predominant cause
Obesity
What happens in T2DM
Eat…food becomes glucose…pancreas secretes insulin…cells are resistant so glucose not absorbed…still feel hungry…eat again…hyperglycemic…hyperinsulinemic…eventual B cell death
Metformin
Improves sensitivity of body tissues to insulin…also lowers glucose production in liver but not actual blood sugar
Sulfonylureas
Increase insulin secretion
Thiazolidinediones
Increase insulin sensitivity but have risks
Adipokines
Cytokines secreted by adipose tissue
Leptin function
Tells brain how much body fat you have (or how much energy storage you have)
What happens to leptin after a few days of overeating?
Sets new baseline level as very hig h
Leptin acts on what in brain?
Hypothalamus
Insulin effect on leptin
Increases secretion
Leptin effect on sinulin
Reduce secretion and gene expression
How does leptin signal reach insulin
Directly from leptin on B cells
Via autonomic nervous system
Leptin effect on pancres
Increase B cell proliferation
Leptin signaling
Leptin binds to receptor, resulting in Jak-Kinases cross-phosphorylating tyrosine residues…STATs dock on tyrosines and are phosphorylated by JAK enzymes…STAT travels to nucleus to affect gene transcription
Effect of STAT in nucleus
Decreased appetite and increased energy expenditure
Leptin insensitivity
Leptin receptor unresponsive to STAT signaling decreases
Results of decreased STAT signaling
Increased appetite
Decreased energy expenditure
Increased obesity and diabetes risk
Repeated activation of _______ leads to leptin resistance
SOCS3
Foxo1 is a product of
AKT - from insulin pathway
How to leptin and insulin pathways interact in T2DM?
Stat5 and STAT3 normally phosphrylate Foxo1 in the nucleus which leads to B cell health…if STAT3 and STAT5 are diminished, then less FOXO1 and worse B cell health
