Flashcards in EXAM1_L89_Signal_transduction_1_2 Deck (34)
types of short distance signaling
Autocrine- same cell type; signal immediate same cells around it. or signal itself.
Paracrine- signal different cell type
Contact dependent signaling
What function? What does it restrict?
autocrine has ligand and receptor on cell surface (69) because they only signal themselves.
paracrine has its ligand directly touching another type of cell's receptor
-Restrains cell growth (lost in cancer)
-Embryogenesis- cell recognition for cells of same tissues
Endocrine signaling . what is ligand/signal? how signal travels? 7 examples of signals.
Hormones-circulatory system- Pit,thyroid,pth,pancreas,adrenal, gonads
Estrogen, progesterone, testosterone, insulin, glucagon, cortisol, epinepherine
Diabetes Type I- autoimmune
Type 2 (IRD)
pancreas cells killed-don't produce ligand (insulin)- never reaches target cells
Target receptors become less responsive to ligand. Pancreas cells exhaust eventually (bcell exhaustion)
Neuronal signaling- type? distance? how?
paracrine (neuron to other cell type)
long distance over axon, short over synapse
2 phases of signaling
-via action potential
hydrophobic signals (steroids) bind carrier proteins outside the cell (to travel in blood), diffuse to inside cell, protein releases ligand then it binds receptor inside the cell
5 steroid hormones
testosterone, estradiol, progesterone, cortisol (glucocorticoid), aldosterone (mineralcorticoid)
steroid hormone action- Which steroid works this way?
1. steroid diffuces into cytoplasm.
2. steroid binds receptor IN CYTOPLASM
3. complex translocated into nucleus
4. complex binds to DNA regulatory site for transcription
CORTISOL works this way
NO synthesis. special feature of NO?
Arginine + NOS > Citrulline + NO
SOLUBLE ! diffused through cytoplasm and plasma membranes!
5 steps of Signaling by NO
1. Nerve rel Ach ligand to endothelial cell receptor
2. binding initiates signal cascade activating NOS
3. NO diffuses out of endothelium into smooth muscle
4. NO+iron bind Guanyl cyclase to make cyclic GMP
5. cGMP initiates cascade to relax smooth muscle
Nitroglycerin to NO
Nitro into>endothelium makes NO (argenine + NOS)
NO/iron bind GC to make cGMP
cGMP cascade signals smooth muscle dilation relieves symptoms of angina
what three AA's can bind a phosphate from kinase?
Tyrosine, Threonine, Serine;
steric hinderance determines residue to be phosphorylated
Two types of receptors for phosphorylation cascades?
like a button/switch to start phosphorylation signal that goes through a circuit.
FAST- & Amplify signal
4 Kinase targets- functions
1. other kinases- rapid amplification
2. phosphatases- dephosphorylate
3. metabolic enzymes- alter activity
4. transcription factors- alter gene expression
GPCR and RTK bind what type of ligands? Why is this important? How will they test me on this?
1. ligands Encoded by genes (glucagon, insulin)
2. made by enzymatic reactions (ntm, ach, epinep)
mediate responses to hormones, ntms and local mediators
Where do growth factors bind?
Ga-S, Ga-I, Ga-q What is target cell? function?
Gai- Adenylate Cyclase (inhibit)
Gas- Adenylate Cyclase (stimulate)
Gaq- Phospholipase C
Ga-s Adenylate cyclase activity
1. Ligand binds
2. Ga-s binds GTP->stim Adenylate cyclase
3. AC (4atp) make cAMP >5 cAMP > PKA > protein kinase cascade
how does cAMP carry a signal? remember the picture of PKA (tetramer) reg/cat units
4 cAMP bind to 2 regulatory subunits of PKA and two catalytic units of PKA dissociate and Kinase activity of PKA is now ACTIVE.
Turning down cAMP signal?
cAMP phosphodiesterase converts cAMP to AMP.
-levels of cAMP in cell depend on balance between Adenylate cyclase and cAMP phosphodiesterase activity
a1-ga-q (phospholipase c)
a2-ga-i (adenylate cyclase)
b1-ga-s (adenylate cyclase)
b2-ga-s (adenylate cyclase)
Adding ADP-Ribose to arginine on Ga-s(cholera)/Ga-i (pertussis)
In both cases- Adenylate cyclase activity is INCREASED
adp-ribosylated Ga-s can't hydrolyze GTP resulting in constant signaling of adenylate cyclase
(cAMP production Stuck ON)
adp-ribosylated Ga-i can't release GDP and can't function to inhibit adenylate cyclase activity
(cAMP production Stuck ON)
a1- adrenergic receptor activation Ga-q activation of phospholipase C
1. epinephrine binds a1 receptor on target cell
2. signal Ga-q binds GTP and activates phospholipase c
3. Phospholipase c cleaves PIP2 (dag stays membrane)
4. IP3 binds Ca receptor on ER and floods Ca cytosol
5. Ca binds PKA and they bind DAG at membrane (ACTIVE)
6. Ca binds calmodulin>wraps CaM Kinase II>autophosphorylates
found in brain, important for memory/learning
Receptor Tyrosine Kinases-
structure of insulin receptor?
bind ligand outside- phosphorylate signal inside
Growth factors- use RTK
Inactive Insulin receptor is a dimer of ab subunits linked by disulfide bonds
RTK Signaling step by step
1. ligand (growth factor) binds RTK
2. two monomeric receptors dimerize
3. tyrosine residues in cytosol autophosphorylize each other
4. phosphrltn alters Charge and conformation & makes new binding site
5. GRB2 binds phosphotyrosine and SOS protein
6. SOS binds RAS and binds GTP so RAS ACTIVATED
7. RAS now starts MAPK cascade
RTK signaling simple
1.- GF binds RTK
2. RTK autophosphorylates binds GRB2/SOS/RAS/GTP
3. RAS now active- activates RAFK starts MAPK cascade
MAPK pathway purpose>
alter gene expression, cell division, cell survival
Signaling mechanisms of metabolic hormones
Signal receptor /location/ affect:
Epi-Ga-s (adipose, muscle)- cAMP/PKA
Glu-Ga-s (liver)- cAMP/PKA
Insulin-RTK(adipose,liver,muscle)- Tyrosine phosphorylation
a1-adrenergic GPCR- GTPase? what does it directly activate? 1st kinase in pathway? cytoplasmic effectors?
Means of shutdown?
Ga-Q- phospholipase C- PKA-(IP3, Ca,Calmodulin)- GTP hydrolyzed by Ga-Q; Ca-ATPase pumps back to ER; Phosphatases
B-adrenergic GPCR-GTPase? directly activates? 1st kinase in pathway? cytoplasmic effectors? shutdown?
Ga-S- Adenylate cyclase- PKA-cAMP/PKA- GTP hydrolyzed by Ga-S; cAMP phosphodiesterase; phosphatases