Lecture 7

Question 1

Receptor desensitization

Answer 1

a decrease in cellular responsiveness following chronic or repeated exposure to agonist

Question 2

receptor desensitization is _____________ response to avoid _______________

Answer 2

adaptive

over-stimulation

Question 3

homologous desensitization

Answer 3

Receptor activation-dependent regulation of receptors
Only the GPCR that is being activated becomes desensitized
Mediated by agonist-induced activation of the same receptor.
The agonist desensitizes target cells only to itself

Question 4

Heterologous desensitization

Answer 4

▪ Receptor activation-independent regulation of receptors
▪ Multiple receptors for the same G protein are desensitized
▪ Caused by activation of a different receptor or through a pathway that is common to many receptors
▪ One ligand desensitizes target cells to other ligands

Question 5

what are the steps of homologous desensitization

Answer 5

uncoupling, sequestration and internalization, Down regulation

Question 6

_____________ is a functional desensitization
often mediated by ___________ modification of
the receptor to alter its ability to signal

Answer 6

uncoupling

covalent

Question 7

what is Endocytosis step of homologous desensitization

Answer 7

Sequestration & Internalization

Question 8

how do you downregulate receptors?

Answer 8

degradation and endocytosis

Question 9

EC50 during uncoupling shifts to _________

Answer 9

right

Question 10

uncoupling is mediated by phosphorylation by ____________

Answer 10

second messenger kinases PKA, PKC

GRK
G protein Receptor Kinases

Question 11

GRKs only phosphorylate ____________ receptor – makes this specific to only the activated receptor (homologous)

Answer 11

agonist-bound

Question 12

__________ binds to the phosphorylated receptor

where does it bind

Answer 12

β-arrestin

β-arrestin binds to the part of receptor where the G protein

which blocks G protein interaction & activation

Question 13

β-arrestin

Answer 13

is a trafficking protein

mediates delivery to clathrin-coated pit

Question 14

explain
Receptor phosphorylation is involved in both heterologous and
homologous desensitization

Answer 14

▪ Homologous: GRK phosphorylates only the activated GPCR

▪ Heterologous: Second messenger Kinases (PKA, PKC)

Question 15

explain how Heterologous Desensitization by Second Messenger Kinases

Answer 15

▪ PKA/PKC cannot distinguish agonist-occupied from unoccupied
receptors, thus leading to desensitization of multiple receptors in
addition to the one being activated

Question 16

Heterologous desensitization by PKA or PKC phosphorylation does
not usually lead to _____________

Answer 16

β-arrestin binding and receptor internalization

Question 17

PKA will phosphorylate _____ receptors

Answer 17

Gs coupled

Question 18

PKC will phosphorylate _________ receptors

Answer 18

Gq coupled

Question 19

How do we visualize receptor localization?

Answer 19

Use of GFP-tagged receptors to monitor localization, internalization and trafficking

Question 20

what are the dual Roles of GRKs and β-arrestin

Answer 20

Classic role of GRKs and β-arrestin in desensitization and internalization

Newer recognized role:
β-arrestin can also send signals independent of the G-protein

scaffolding protein
for assembling a signaling
complex that sends G-protein
independent signa

Question 21

what does biased Agonism or Signal Trafficking mean

Answer 21

Different agonists can put the receptor in a 
conformation that is biased towards a 
particular signal to send:
▪ G protein and β-arrestin signals
▪ G protein signals only
▪ β-arrestin signals only

Question 22

explain Multiple Active Receptor Conformations (Bias)

Answer 22

Conformation-specific agonism
(or conformation-selective agonism)
▪ Receptors have many conformation
Agonists stabilize one of the active 
conformations
▪ Partial agonists stable partially active 
conformations
▪ Antagonists block all actions, do not 
alter the equilibrium among 
conformations at all

Question 23

Biased agonism vs subtype-selective agonism

Answer 23

Biased agonist generates two alternate signals
from a single receptor molecule

Subtype-selective agonists can generate
different signals, but they do it by binding to
different receptor molecules.

Question 24

List Signal Localization

Answer 24

1. PDEs to keep cAMP (and cGMP) signals localized (previous lecture)
2. AKAPs to localize PKA (and PDEs) (previous lecture and next slide)
3. Membrane microdomains
4. Calcium channels near Calcium-sensitive Adenylyl cyclase

Question 25

explain AKAP

Answer 25

▪ AKAP complex at plasma membrane with PKA but also PKC and protein phosphatase 2B
▪ Two different protein kinases plus a phosphatase to remove the phosphates that the
kinases add

Question 26

what is caveolae/rafts

Answer 26

Specialized membrane

signaling domains