Lecture 13: Signal Transduction IV Flashcards
Beta-blockers
-effect Gs pathway
-norepinephrine cannot bind
= no response (pain, figh/flight)
cAMP mediated signaling RECAP
- Adenylate cyclase makes ATP to cAMP
- cAMP subunits split into 2R+4cAMP and 2C
- 2C (PKA) makes ATP to ADP (phosphorylyzes)
= response
Gaq signaling
- phospholipase C-B
- Diacylglycerol or IP3
- PKC or IP3 receptor
- Ca+2
Gq
-muscarinic
-neurotransmitters
-acetylcholine, ANg II receptors
Gq signaling
- Ga stimulates phospholipase C-B to hydrolyze PIP2 = IP3 and DAG
Gq signaling from IP3
- IP3 gates ca2+ release from ER ion channel
- Ca2+ binds PKC
- PKC travels to membrane
- PKC binds DAG and is activated
Gq signaling from DAG
- binds to PKC
- Phosphorylate protein (add P)
- response
Maintaining low cytoplasmic Calcium
-there is more calcium outside cell (10^4 difference)
-active transport:
1. NCX:sodium-calcium exchanger (antiport)
2. Ca2+ ATPase
3. SERCA: sarco/endoplasmic reticulum Ca2+ ATPase (calcium into ER)
Calmodulin (CaM)
-binds Ca2+ at 2 terminal EF hand domains (4 calcium binded 2 at each domain)
-conformational change exposes hydrophobic surfaces
calmodulin-dependent kinase
-binds to alternate CaM conformation
CaM alternate conformation (after change)
-binds many signaling protiens
-alters CaM kinase activity including autophosphorylation activity
CaM + Ca2+
- conformational change
- binds protein to activate
- autophosphorylation to fully active protein
- lose calcium = CaM kinase
- inactivated by protein phosphatase
What is likely affinity of Ca2+
10^-6
-close to concentration
KD of calmodulin for Ca higher than concentration of Ca
not binding Ca2+
calcium increase
activates Gaq
phospholipid-derived signaling
-phospholipase activation by GPCRs and RTKs
-hydrolyze or phosphorylate
-phospholipase C
phospholipid receptor tyr kinases (RTK)
-phosphatidylinositol 3 kinase (PI3K)
Phospholipase C hydrolysis
-breaks bond between glycerol and inositol of PIP2
PIP2
phosphatidylinositol 4,5-bisphosphate
DAG
diacylglycerol
IP3
inositol 1,4,5-trisphosphate
PLCB
-activated by interaction with trimeric g proteins
-GPCR
PLCy
-activated by tyrosine phosphorylation
-RTK
Phosphatidylcholine (PC) hydrolysis
-phospholipase D
= phosphatidic acid (PA) and choline
-PA converted to DAG
PI3 kinase
-phosphorylation of 3’OH PIP2 to PIP3
PIP3
-2nd messenger
-recognized by pleckstrin homology domain (PH domains)
PIP3 signaling
- activated RTK + P2 + activated PI3 kinase
- = PIP3
- PIP3 recognized by PH domain of protein
- =phosphorylation and activation of protein
- dissociation
PI3K/AKT pathway (protein Kinase B (PKB signaling))
-PIP3 second messenger
-promotes cell survival
-repress cell-death pathways
-regulate glucose transport and glycogen metabolism
-often altered in cancer