signaling: receptors

Question 1

G protein coupled receptors have ____transmembrane domains arranged into a______.

Answer 1

7

barrel-like pore where the ligand binds

Question 2

GPCR amino terminus extends into the____while the carboxyl terminus extends into the ____.

Answer 2

ECF

cytoplasm

Question 3

Loops that extended into the cytoplasm (i-loops) confer

Answer 3

specificity for the G protein binding

Question 4

Alpha unit that binds

Answer 4

GDP/GTP

Question 5

Beta/Gamma unit

Answer 5

that act as one

Question 6

Ligand binding to the receptors gives it the ability to

Answer 6

make the reaction that exchanges GDP for

GTP on the alpha unit more favorable

Question 7

______ is the rate-limiting step of the cascade, this allows for the activation of the _____

Answer 7

nucleotide exchange

cellular pathway

Question 8

This reaction can also be catalyzed with the assistance of a ____

Answer 8

guanine nucleotide exchange factor (GEF).

Question 9

Once the alpha unit is bound to GTP, it

Answer 9

dissociates from the beta-gamma unit and both are available to act on effector proteins.

Question 10

The alpha unit has an intrinsic

Answer 10

GTPase activity that eventually hydrolyzes the GTP to GDP (this can be assisted by GTPase activating proteins or GAPs).

Question 11

Once the alpha unit is again associated with GDP, it can be recycled back to the

Answer 11

membrane and G protein coupled receptor.

Question 12

Second messengers are molecules that relay _____ They often are involved in _____

Answer 12

signals from the cell surface to targets inside the cell.

amplification of the signal.

Question 13

examples of 2nd messengers

Answer 13

1. B-adrenergic receptors
2. a1 adrenergic receptos
3. m2 muscarinic cholinergic receptors
4. m2 muscarinic cholinergic receptor

Question 14

Beta adrenergic receptors (heart):

Answer 14

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.

Question 15

Alpha1 adrenergic receptors (peripheral vasculature):

Answer 15

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.

Question 16

m2 muscarinic cholinergic receptors (sympathetic input):

Answer 16

acetylcholine binds the receptor,
activating the Gs protein with GTP which binds AC and increases cAMP
leading to increased heart rate.

Question 17

m2 muscarinic cholinergic receptors (parasympathetic input):

Answer 17

acetylcholine binds the receptor,
activating the Gi protein with GTP which binds AC and prevents an increase in cAMP
leading to decreased heart rate.

Question 18

Both of these G proteins (Gi and Gs)

Answer 18

can be active at the same time
Both can bind AC
whichever has the more dominant signallying “wins” and effects heart rate more.

Question 19

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 _____

Answer 19

receptor desensitization

GRK.

Question 20

GRK phosphorylates the _____

This results in its _____

Answer 20

cytoplasmic loops of the G protein coupled receptor

inability to interact with G proteins.

Question 21

GPCR’s these phosphorylated residues recruit a

Answer 21

protein called beta arrestin.

Question 22

Binding of beta arrestin further prevents G proteins from

Answer 22

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.

Question 23

The cell becomes less sensitive to ligand because of _____. These internalized receptors can then be _____

Answer 23

fewer receptors

degraded or re-sensitized and recycled.

Question 24

drugs that act through modulating different steps in a receptor-G protein-second messenger signaling cascade.

Answer 24

1. metoprolol
2. prazosin
3. atropine
4. PDE inhibitors

Question 25

Metoprolol:

Answer 25

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.

Question 26

Prazosin:

Answer 26

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.

Question 27

Atropine:

Answer 27

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.

Question 28

PDE inhibitors – target

Answer 28

These target the phosphodiesterases (PDE) of the message pathway to activate signaling.

Question 29

PDE inhibitor examples

Answer 29

Caffeine, Theophyline, Milinirone, Rolipram,

Question 30

PDEs degrade cAMP by:

Answer 30

cleaving it to AMP, which is not capable of activating PKA, and thus terminate signaling

Question 31

Many of these PDEs are constitutively ____

Answer 31

active.

Question 32

By inhibiting the terminator of the signal, PDE inhibitors are able to

Answer 32

extend signaling.

Question 33

agonist:

Answer 33

activates receptor

Question 34

antagonist

Answer 34

inactivates receptor

Question 35

Adrenergic receptors:

Answer 35

bind norepinephrine.

Question 36

Muscarinic cholinergic receptors:

Answer 36

bind acetylcholine.