Signaling: receptors Flashcards
Describe the basic structure of G-protein coupled receptors (a family of over 200 membrane receptors)
- 7 trans membrane domains
- N terminus outside
- C terminus inside
- trans mem. 1 by trans. mem 7 creating a barrel like structure
- Bind ligands in “small pocket” of alpha helicies just below surface of cell membrane
What is the conformation of intracellular G-proteins when the GPCR is not bound to an agonist?
3 subunits:
Alpha
Beta & Gamma (never found alone)
Bound to GDP
What happens when an agonist binds to the GPCR?
Conformational change!
GDP released from G-protein subunits -> GTP bound by G-protein subunits (at alpha)
=> G-protein is ACTIVATED
What is the next step once the G-protein is activated?
Activation reduces affinity of Alpha and Beta-gamma subunits -> dissociate and diffuse along plasma membrane (ligand bound)
Alpha and beta-gamma each interact with unique effectors
What is another function of the alpha G-protein subunit? (beyond interacting with effectors)
Acts as GTPase
- “built in timer”
- Once it hydrolyzes GTP -> GDP => inactive
- Inactive form has increased affinity for beta-gamma subunit -> will re-bind to G-protein Coupled receptor
(if agonist is still present cycle can restart)
How does the pertussis toxin affect the G-protein?
Binds/ inserts ADP-ribose into Alph-subunit => locks inactive confirmation
(prevents receptor coupling)
How does cholera toxin affect the G-protein?
Inserts ADP-ribose near hydrolyzing site of alpha-subunit => prevents hydrolysis of GTP -> keeps Alpha in active form -> over expressed
What is the beta-adrenergic GCPR pathway in response to an agonist? (in the heart)
Agonist (NE, epinephrine, isoproterenol) -> Activate alpha Gs -> Gs binds Adenylate cyclase (AC) -> Increase levels of cAMP [SECOND MESSENGER] -> cAMP activates Protein kinase A (PKA) -> PKA phosphorylates (opens) Ca+ channels
=> [Ca2+] increases & HR & BP increase
What are some antagonists of the Beta-adrenergic GCPR? What do they do?
Beta-blockers => decrease HR and BP
propanolol
metoprolol
What is the alpha-adrenergic GCPR pathway in response to an agonist? (in peripheral vasculature)
Agonist (NE, epinephrine, phenylephrine) -> activate alpha Gq -> Gq binds phospholipase c (PLC) -> PLC cleaves PIP2 -> IP3 & DAG [SECOND MESSENGERS]
IP3 -> binds receptor on ER -> releases Ca2+
DAG -> activates PKC -> PKC stimulates L channel (L-ch) -> allows Ca2+ in
=> [Ca2+} increases - smooth muscle contract - decreased blood flow to periphery - Increase BP
What are some antagonists of the Alpha-adrenergic GCPR pathway? What do they do?
Alpha- blockers => decrease BP
prazosin
How does the m2-muscarinic cholinergic receptor inhibit Gs in the heart?
Agonist (acetylcholine, muscarine) bind M2AchR -> activate Gi -> Gi agonizes/ inhibits Gs-> dominant inhibition is possible ->
cAMP degraded by phosphodiestreases (PDEs) -> AMP (does not activate PKA) -> no signaling to increase Ca2+
What types of substances can inhibit phosphodiesterases- PDEs? (maintain cAMP levels)
Caffeine/ theophyline
Millinirone (PDE3)
Rollpram (PDE4)
Viagra
How does the M2AchR affect the beta-gamma pathway?
agonist (Ach) activates Beta-Gamma -> Beta-gamma binds and activates K+ channel -> K+ exits cell, decreases Ca2+ influx, hyperpolarizes cell
=> decreases HR & contraction
How does the B2 GPCR in the lung differ from the B1 GPCR in the heart and Gs GPCR in the periphery?
Same initial pathway:
agonist -> B1 alpha activation -> cAMP hydrolysis -> PKA activation
=> INHIBITS SMOOTH MUSCLE CONTRACTION - BROCODILATION
- same in blood vessels to lung, heart and muscle
