signaling: receptors Flashcards
G protein coupled receptors have ____transmembrane domains arranged into a______.
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barrel-like pore where the ligand binds
GPCR amino terminus extends into the____while the carboxyl terminus extends into the ____.
ECF
cytoplasm
Loops that extended into the cytoplasm (i-loops) confer
specificity for the G protein binding
Alpha unit that binds
GDP/GTP
Beta/Gamma unit
that act as one
Ligand binding to the receptors gives it the ability to
make the reaction that exchanges GDP for
GTP on the alpha unit more favorable
______ is the rate-limiting step of the cascade, this allows for the activation of the _____
nucleotide exchange
cellular pathway
This reaction can also be catalyzed with the assistance of a ____
guanine nucleotide exchange factor (GEF).
Once the alpha unit is bound to GTP, it
dissociates from the beta-gamma unit and both are available to act on effector proteins.
The alpha unit has an intrinsic
GTPase activity that eventually hydrolyzes the GTP to GDP (this can be assisted by GTPase activating proteins or GAPs).
Once the alpha unit is again associated with GDP, it can be recycled back to the
membrane and G protein coupled receptor.
Second messengers are molecules that relay _____ They often are involved in _____
signals from the cell surface to targets inside the cell.
amplification of the signal.
examples of 2nd messengers
- B-adrenergic receptors
- a1 adrenergic receptos
- m2 muscarinic cholinergic receptors
- m2 muscarinic cholinergic receptor
Beta adrenergic receptors (heart):
Norepinephrine binds the receptor, causing GDP/GTP exchange and the activation of the Gs alpha unit which binds to adenylyl cyclase (AC) to activate it.
AC creates cAMP, a second messenger, increasing levels in the cell, which in turn activate protein kinase A (PKA).
PKA phosphorylates Ca channels, leading to influx of Ca.
These steps lead to contraction of cardiac muscle.
Alpha1 adrenergic receptors (peripheral vasculature):
Norepinephrine binding causes the exchange of GDP for GTP on Gq alpha unit.
Gq-GTP interacts with the PLC molecule which cleaves minor membrane lipid PIP2.
This causes an increase in the second messengers DAG and IP3 both which eventually stimulate Ca channels and contraction of smooth muscles.
m2 muscarinic cholinergic receptors (sympathetic input):
acetylcholine binds the receptor,
activating the Gs protein with GTP which binds AC and increases cAMP
leading to increased heart rate.
m2 muscarinic cholinergic receptors (parasympathetic input):
acetylcholine binds the receptor,
activating the Gi protein with GTP which binds AC and prevents an increase in cAMP
leading to decreased heart rate.
Both of these G proteins (Gi and Gs)
can be active at the same time
Both can bind AC
whichever has the more dominant signallying “wins” and effects heart rate more.
The signaling pathway that activates G proteins, also activates _____. One of the binding partners of the beta-gamma subunit after it dissociates from the alpha-GTP unit is a kinase called _____
receptor desensitization
GRK.
GRK phosphorylates the _____
This results in its _____
cytoplasmic loops of the G protein coupled receptor
inability to interact with G proteins.
GPCR’s these phosphorylated residues recruit a
protein called beta arrestin.
Binding of beta arrestin further prevents G proteins from
associating with the receptor, preventing further signaling through a particular receptor.
This also acts as an adaptor for endocytic machinery, which causes internalization of the entire receptor.
The cell becomes less sensitive to ligand because of _____. These internalized receptors can then be _____
fewer receptors
degraded or re-sensitized and recycled.
drugs that act through modulating different steps in a receptor-G protein-second messenger signaling cascade.
- metoprolol
- prazosin
- atropine
- PDE inhibitors
Metoprolol:
is a antagonist of the beta adrenergic receptor which blocks the activation of the G protein with GTP.
Thus, it prevents an increase in cAMP in response to Norepinephrine and lowers heart rate.
Prazosin:
is an antagonist of the alpha1 adrenergic receptor which prevent Gq-GTP from interacting with PLC.
This in turn prevents the creation of DAG and IP3 receptors.
Atropine:
is an acetylcholine antagonist that prevents activation of Gi protein with GTP and thus is an antagonist of parasympathetic signaling. This results in a shift of balance with the Gs protein, whereby Gs “wins” and cAMP levels increase, increasing muscle contraction of the heart.
PDE inhibitors – target
These target the phosphodiesterases (PDE) of the message pathway to activate signaling.
PDE inhibitor examples
Caffeine, Theophyline, Milinirone, Rolipram,
PDEs degrade cAMP by:
cleaving it to AMP, which is not capable of activating PKA, and thus terminate signaling
Many of these PDEs are constitutively ____
active.
By inhibiting the terminator of the signal, PDE inhibitors are able to
extend signaling.
agonist:
activates receptor
antagonist
inactivates receptor
Adrenergic receptors:
bind norepinephrine.
Muscarinic cholinergic receptors:
bind acetylcholine.
