Intracellaru Siganlling Transduction Flashcards
What are the intracellular signalling molecules downstream of GPCR?
C-AMP, Ca2+, diacylglycerol, ion channels
How is cAMP level regulated?
C-AMP is produced by adenilate cyclase which increases c-AMP levels. When CAMP levels raise,
c-AMP activates PKA. PKA phosphorylates and activates a phosphodiesterase which lowers c-AMP levels (negative feedback).
What are the target of GPCR?
Adenyl cyclase, phospholipase C-Beta, ion channels.
How is the GPCR signalling shut down?
Arrestin binds to phosphorylated GPCR
How are RTK activated?
Dimerisation
What does ”amplification” mean?
It means that the strength of the signal is no longer proportional to receptor binding
What do Some GPCR do ?
Some GPCRs stimulate adenylyl cyclase; the resultant production of cAMP activates protein kinase A…
and active protein kinase A phosphorylates the transcription factor, CREB
Flight OR fight
Example: effect of adrenalin on glycogen breakdown
Fight of flight reaction: You suddenly have the energy to run as fast and as hard as you could, as adrenalin is breaking down every molecule of glycogen in your muscles and liver.
G couples and Ion phospholipids
GPCR can activate phospholipase C-𝝱 (PLC𝝱). This cleaves PI (4,5)P2 in IP3 and diacylglycerol.
The signalling pathways splits in two branches: - IP3 reaches the ER and binds and open IP3-gated Ca2+ release channel in the ER membrane. Ca2+ is released in the cytosol and induces translocation of protein kinase C (PKC) from the cytosol to the membrane. -
PKC is activated by the concerted action of Ca2+ and diacylglycerol. Once activated PKC phosphorylates specific targets
Example of GPCR signalling: response to serotonin
When the nerve cells are incubated in vitro with serotonin, the level of cAMP increase rapidly. (the cell has been loaded with a fluorescent dye that changes its fluorescence when it binds cAMP).
cAMP also induces gene transcription in the target cells. This response requires more time. This process is thought to play an important role in some forms of learning and memory in response to somatostatin.
Example of GPCR signalling: response to acetylcholine
In the skeletal muscle acethlycoline induces directly activation of Ca2+ channel. This induces muscle contraction. In the heart muscle instead acethlycoline induces activation of K+ channel via GPCR. This has a global effect of reducing the heart rate.
The The responses are different because the intracellular signalling is different!
Example of GPCR signalling: response to acetylcholine
In the endothelial cells acethylcoline induces activation of GPCR through phospholipids. The overall effect is the activation of NO synthase.
NO diffuses across the membranes and activates guanylyl ciclase in smooth muscle cells, inducing an increase in cGMP. This induces the cells to relax.
Control of the signalling pathways
Negative feedback arrangement on PKA Among the targets that PKA phosphorylates and activates is the phosphodiesterase which lowers cAMP level. This negative feedback converts what might be a prolonged response in a local short one.
Summary of GCPR
GPCR can directly inactivate or inactivate plasma membrane bound enzymes or ion channels via G proteins.
When activated the GPCR undergoes a conformational change that activates its ⍺ subunit, thereby triggering release of a 𝝱𝞬 complex.
Some GPCR activate or deactivate adenylyl cyclase, other phospholipase C, other ion channels.
The main targets of GPCR are protein kinase A (PKA), protein Kinase C (PKC) and Ca2+ calmodulin dependent protein kinase (caM-kinase)
GPCR are inactivated by phosphorylation
Type of Enzyme Coupled Receptors
Receptor Tyrosine Kinase (RTKs)
Tyrosine Kinase associated receptor
Receptor Serine-Threonine Kinase
