GPCR Signaling Flashcards
Endocrine signaling - what is it? Examples?
Hormone from distant tissue enters blood to reach distant target cell; seen in metabolic pathways
Ex) Insulin/glucagon; pituitary gland
Paracrine signaling - what is it and what’s an example?
Signaling and responding cells are very close or adjacent.
Ex) Growth factors, smooth muscle relaxation
Autocrine signaling
Signaling cell and the responding cell are the same cell
Seen in many proliferating cell types
When is the G<em>a</em> subunit active?
Active when bound to GTP
Summarize the GPCR Signaling pathway
- Ligand binds GPCR, changing its conformation
- GPCR activates the trimeric G protein by triggering dissociation of GDP
- Ga binds GTP and leaves the receptor to activate an effector
- Effector hydrolyzes Ga’s GTP and generates a second messenger.
- Second messenger activates some intracellular and downstream signaling pathway while the ianctivated Ga returns to the By subunits at the GPCR
GPCR > Adenylyl cyclase (effector) > ____ > ____
GPCR > Adenylyl cyclase (effector) > cAMP (2nd msger) > PKA pathway
GPCR > Guanylyl cyclase (effector) > ____ > ____
GPCR > Guanylyl cyclase (effector) > cGMP (2nd msger) > PKG pathway
GPCR > Phospholipase cyclase (effector) > ____ > ____
GPCR > Phospholipase C (effector)
> DAG (2nd msger) > PKC pathway
&
> IP3 (2nd msger) > Ca2+ release from ER (also considered a 2nd msger)
B adrenergic receptor vs a adrenergic receptor impact on cAMP
B-adrenergic (epinephrine) receptor activates G<em>as</em> to activate adenylyl cyclase and increase cAMP
a-adrenergic receptoractivates Gai to activate adenylyl cyclase anddecrease cAMP
GPCR siganling activates or shuts down a pathway by
Stimulating or inhibiting an effector –> increases or decreases the 2nd msger
Example of how different tissues respond differently to the same signal and GPCR pathway - Epinephrine
Epinephrine causes metabolism of fats in adipose tissue; breakdown of glycogen in liver and muscle; increases contractile rate in cardiac muscle; and fluid secretion in the intestine
PKA pathway
- cAMP binds PKA’s regulatory subunits
-
PKA’s catalytic subunit enter the nucleus to phosphorylate CREB
- Can also phoshporylate MAPK to affect changes in gene expression
- CREB is a tf that binds to CRE response elements
- CREB-binding proteins (CBP)/p300 tf’s bind CREB and associate with transcriptional machinery to mediate transcription of CRE-containing genes
Cholera & diarrhea
Maintains G<em>as</em> -> adenylyl cyclase -> cAMP -> PKA -> CFTR channel
Opening the CFTR channel in intestinal epithelial cells causes Cl- to flow into the intestinal lumen and water follows –> Watery diarrhea
Bordatella pertussis & Whooping cough
Turns off G<em>ai</em> -> Adenylyl cyclase -> cAMP -> PKA -> CFTR channel
Opening the CFTR channel in the lung causes fluid loss (as mucous secretion) in the lungs, causing whooping cough
What GPCR signaling pathway is involved in normal heart contraction?
B-Adrenergic receptor / cAMP / PKA signaling
How does the B-adrenergic/GPCR/cAMP/PKA signaling pathway cause heart contraciton?
- The PKA pathway causes an intracellular Ca2+ from the sarcoplasmic reticulum into the cytosol.
- Increased cytosolic Ca2+ generates systolic muscle contraction
- Myofibril efflux of Ca2+ back into the SR causes relaxation
Any __crease in the in the relative amplitude or ratio of cytosolic:SR Ca2+ pools weakens subsequent contractions
Decrease
Decreased muscle contraction (systolic dysfunction) results from __creased B-adrenergic GPCR signaling
Increased B-Adrenergic GPCR signaling
Causes impaired Ca2+ release; defective termination of release; and/or defective calcium sequestration (diastolic dysfunction)
How does propranolol work?
Propranolol is a beta-blocker- it inhibits B-Adrenergic signaling to re-establish the proper cytosolic:SR ratios of Ca2+ stores –> improves cardiac contractile function
Smooth msucle relaxation illustrates what type of signaling?
Paracrine signaling among endothelial cells lining blood vessels
What’s the ligand for smooth muscle relaxation?
- Acetylcholine activates PLC to generate IP3 and DAG
- IP3 causes release of Ca2+
- Ca2+ complexes with calmodulin
- Calmodulin-Ca2+ activates nitric oxide synthase
- Nitric oxide synthase produces NO
- NO diffuses to the neighboring smooth msucle cell and activates guanylyl cyclase
- Guanylyl cyclase –> cGMP
- cGMP activates PKG
- PKG causes smooth muscle relaxation and blood vessel dilation
How does phospholipase C activate PKC to phosphorylate target proteins?
- Phospholipase C cleaves PIP2 into DAG and IP3
- IP3 releases Ca2+ from the ER
- Ca2+ brings PKC to the plasma membrane, where it is activated by DAG
