Effector mechanisms Flashcards
A GPCR activates a G-protein which activates an …
Effector
An effector can be … (2)
an enzyme or ion channel
Effectors can be enzymes. Give 4 examples of effectors that are enzymes
Adenylyl cyclase
Phospholipase C
Phosphoinositide 3-kinase (PI3K)
cGMP Phosphodiesterase
What does adenylyl cyclase do?
converts ATP to cyclic AMP (cAMP)
Give 4 examples of effectors that are enzymes, and name their second messengers
- adenylyl cyclase produces cAMP
- phospholipase C produces IP3 and DAG (via PIP2)
Example of ion channel effectors
Voltage-operated Ca2+ channels
GIRKS (G protein-regulated inwardly-rectifying K+ channels)
Describe how adenylyl cyclase is stimulated to produce cAMP (7)
- Agonist binds to the GPCR, activating it
- The GPCR interacts with the G protein (Gs protein with an alpha s subunit)
- This Gs-protein exchanges GDP for GTP
- The active component of the G Protein (αlpha s with GTP bound to it) is released
- That moves along the plane of the membrane, interacts with adenylyl cyclase
and activates it. - Adenylyl cylase then converts ATP to cyclic AMP (the pathway second messanger)
- cAMP can interact with a number of cellular targets to regulate cellular activity e.g. PKA
What is the most important effector of cyclic AMP?
Cyclic AMP-dependant protein kinase (PKA)
Describe how adenylyl cyclase is inhibited from producing cAMP (6)
- Agonist binds to the GPCR, activating it
- The GPCR interacts with the G protein (Gi protein with an alpha i subunit)
- This Gi-protein exchanges GDP for GTP
- The active component of the G Protein (αlpha i with GTP bound to it) is released
- That moves along the plane of the membrane, interacts with adenylyl cyclase
and inhibits the activity of it. - cAMP is thus not produced from ATP so other molecules, eg. PKA, aren’t activated
What does Gs do?
GDP –> GTP on alpha s unit
STIMULATES adenylyl cyclase
ATP –> cAMP
cAMP activates PKA
Gs coupled receptors exampels
B-adrenoreceptors
D1-dopamine receptors
H2-histamine receptors
What do Gi do?
GDP –> GTP alpha i unit
INHIBITS adenylyl cyclase
ATP not converted to cAMP
PKA not activated
Gi coupled receptors examples
a2 adrenoreptors
D2 dopamine receptors
µ-opioid receptors
Cyclic AMP exerts the majority of its actions through …
cyclic AMP-dependent protein kinase A (PKA)
Describe the structure of PKA
Heterotetramer made up of 2 regulatory subunits and 2 catalytic subunits
2 subunits of PKA
2x R (regulatory) 2x C (catalytic)
What does R unit do?
Inhibits PKA by binding to C (catalytic) subunits
What do C units do?
Covalently modify target proteins in a cell via phosphorylation
1) When does cAMP activate PKA?
2) How does cAMP activate PKA?
1) When levels of cAMP are high
2) - When cAMP is high, it binds to R (regulatory) subunits on PKA
- the interactions between the R and C subunits are weakened
- C (catalytic) units are released and now free to phosphorylate target proteins in the cell
What happens when cAMP is low? (2)
- The R subunits of PKA bind to the C subunits
- To inhibit their action of phosphorylating target proteins in the cell
What are the second messengers that are produced from phospholipase C?
- IP3
- DAG
Describe how phospholipase C (PLC) is regulated to produce IP3 and DAG, the 2 second messengers (7)
- Agonist binds to the GPCR, activating it
- The GPCR interacts with the G protein (Gq protein with an alpha q subunit)
- This Gq-protein exchanges GDP for GTP
- The active component of the G Protein (αlpha q with GTP bound to it) is released
- That moves along the plane of the membrane, interacts with phospholipase C and activates it.
- Phospholipase C then interacts with a membrane phospholipid, PIP2
- PLC cleaves PIP2 into IP3 and DAG, its 2 second messengers
How do GaQ work?
GDP –> GTP on alpha q unit
Activates Phospholipase C
PIP2 is cleaved into IP3 and DAG
What do IP3 do? (3)
IP3:
- Moves freely through cytoplasm
- Binds to IP3 receptors on ER
- Opens Ca2+ channels causing Ca2+ to be released into the cytoplasm down its conc. grad.
