Receptors and Cell Signaling

Question 1

Cell Signaling Fast Response

Answer 1

Change in activity or function of enzymes or
proteins in the cell

Question 2

Cell Signaling Slow Response

Answer 2

Change in amounts of proteins by change in
expression of genes

Question 3

Acetylcholine - Different responses in different cells

Answer 3

B) heart muscle cells
relax
C) skeletal muscle cell
contract
D) salivary gland cell
secretion of saliva

Question 4

Ligands

Answer 4

• Can be proteins, small peptides, amino acid derivatives,
hydrophobic molecules (steroid hormones like estrogen)
• Even gases (NO)
• Main categories:
– Small lipophilic molecules: steroid hormones
– Water soluble molecules – hydrophilic – e.g. growth
factors

Question 5

Lipophillic Ligands

Answer 5

Steroids, Thyroid Horome (Thyroxine), Retinoids

Question 6

Hydrophillic Ligands

Answer 6

Acetylcholine, proteins, and polypeptides

Question 7

Steps of G-protein relaying signals

Answer 7

• 1. Ligand binds to receptor
• 2. Conformational change occurs in receptor

• 3. Receptor binds to G protein
GTP bound form is active. — GDP bound is inactive.
• 4. Receptor then acts as a GEF: Guanidine Exchange Factor

• 5. Confirmation of Ga protein is changed such that it kicks out GDP and GTP binds to it

• 6. Ga now becomes active and can bind to
effector molecule and activate effector
molecule
• 7. Effector

Question 8

GEF

Answer 8

Guanine nucleotide exchange factors

activate monomeric GTPases by stimulating the release of guanosine diphosphate(GDP) to allow binding of guanosine triphosphate (GTP).

Question 9

cAMP activates this

Answer 9

cAMP dependant Protein Kinase A (PKA)

2 Regulatory subunits and 2 catalytic subunits.

binding of 2 cAMP molecules to regulatory subunits of
tetramer results in release of active C subunits

Question 10

Cholera Mechanism

Answer 10

• Cholera toxin modifies G protein by
keeping the Ga in the GTP active form
indefinitely
• Leads to 100 fold increase in cAMP
• PKA phosphorylates the CFTR Cl- channel
• Leads to secretion of water

• Water and Cl- come out together

Question 11

Desensitization: ability to turn off or reject the
signal - Important: cell cycle – cancer

Answer 11

– **Potentiate = turn up
– **Attenuate = turn down

Question 12

Examples of desensitization

Answer 12

• Remove the signaling molecule:
phosphodiesterases will remove cAMP/cGMP
• Receptor sequestration: endosome
• Receptor destruction: endosomes + lysosomes
(proteases)

Question 13

GAP Proteins

Answer 13

GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event.

Question 14

GRKs

Answer 14

• There are proteins called GRKs: G
protein receptor kinases
• GRKs phosphorylate the receptor
such that another protein called
arrestin will bind to the to the 3rd
intracellular loop and prevents Ga
from interacting with the third loop
• Result is that Ga-GDP does not get
converted to Ga-GTP

Question 15

Gi(alpha)

Answer 15

Inhibitory Galpha that inhibts AC.

Question 16

Gqα G-proteins

Answer 16

– Activates PLC
instead of AC

• Phoshoplipase C cleaves
a membrane protein called
PIP2
• Produces IP3 and DAG 2nd
messengers
• IP3: inositol 1,4,5-
triphosphate (diffusible)
• DAG: 1,2-diacylglycerol
(membrane bound)

IP3 triggers release of Ca2+ from endoplasmic reticulum
(calcium storage in ER)
• IP3 does this by binding to an IP3-gated Ca2+ channel +
triggers opening
• Ca2+ released into cytosol so you get increased calcium
concentration
• Ca2+ is a second messenger too!
• IP3 is done.

• Now high cytosolic calcium concentrations
• Both Ca2+ and DAG bind to another protein kinase
called protein kinase C (PKC)
• Conformational change occurs in PKC and it is
activated
• PKC phosphorylates a variety of membrane and
cytoplasmic substrates

Question 17

Receptor Tyrosine Kinases

Answer 17

• Receptor tyrosine kinases are used for response to growth factors: mediate growth factor signals • Growth factors are proteins released by cells to promote growth of other cells
• Autophosphorylation causes the receptor to act as a scaffold to recruit other proteins to the plasma membrane
• Receptor does not bind to G protein but receptor binds to proteins with domains called the SH2 domains (src homology) – SH2 domain binds to phosphotyrosine
• Src is the first oncogene discovered

Question 18

In mammals the SH2

Answer 18

Grb2 (adaptor protein)

Question 19

Receptor Tyrosine Kinase Activity

Answer 19

• Ligand = BOSS

• RTK binds to SH2 domain of Grb2
• SH3 of Grb2 binds to prolines in SOS

• SH3 of Grb2 binds to prolines in SOS (RAS GEF) which then binds to
Ras (small monomeric G protein – small GTPase)

• Ras binds Raf and then things get insane

Question 20

What is downstream of Ras?

Answer 20

Ras-> (MAP KKK) Raf -> (MAP KK) Mek -> (MAP K) Erk

Question 21

Insulin signaling

Answer 21

RAS-dependent and RAS-independent signaling via RTK

• *Intermediate scaffold**
• IRS-1

binds GRB-2 or PI3K

GRB-2 -> RAS -> Alterations in gene transcription

PI3K - > PKB -> Alterations in protien and enzyme activity

Question 23

JAK-STAT Receptors

Answer 23

More direct route for impacting
transcription

1. ) receptors bind cytokines and dimerize then get Jaks attached.
2. ) Jaks phosphorylate eachother and the receptors.
3. ) Receptors bind STATS and then phosphorylate them.
4. ) STATS break off and dimerize and go to the nucleus.

Question 24

Serine-threonine receptors & Smad

Answer 24

More direct route: R-Smad = receptor specific
Smad and forms complex with Co-Smad:
common Smad

1. ) Ligand binds to serine threonine receptor
2. ) Dimerize and serine is phosphorylated
3. ) Type 1 receptory phosphorylates R-SMAD
4. ) R-SMAD (phosphorylated) and CO-Samd dimerize and then go to the nucleus.