Cell Signaling - Lectures 3 - 4

Question 1

What are the 4 types of signaling receptors?

Answer 1

Ligand-activated ion channels
G-protein coupled receptors
Tyrosine kinase receptors
Ligand-activated transcription factors

Question 2

What are the two sites of ligand-activated ion channels?

Answer 2

Plasma membrane

Organelle membranes

Question 3

Ligand-activated ion channels

Answer 3

Multisubunit proteins that produce graded potentials

Question 4

How does a ligand-activated channel depolarize, and what molecules trigger this event?

Answer 4

Let in Na

Acetylcholine, Glutamate, Serotonin

Question 5

How does a ligand-activated channel hyperpolarize, and what molecules trigger this event?

Answer 5

Let in Cl

Glycine, GABA

Question 6

Activating and inhibiting ligand activated plasma membrane ion channels is the basis of what?

Answer 6

Synaptic transmission of nerve impulses

Question 7

What are some mechanisms of drugs that target ligand activated ion channels?

Answer 7

• Mimic or block the actions of neurotransmitters
• Block the channel
• Affect transmitter reuptake
• Affect transmitter metabolism

Question 8

IP3

Answer 8

Mediated Ca release from the ER internal store

Question 9

What is the concentration of Ca in the cytoplasm at rest?

Answer 9

10-100 nM

Question 10

What is the concentration of Ca in the cytoplasm following IP3-mediated release?

Answer 10

500-1000 nM

Question 11

What happens when the Ca concentration of the cytoplasm increases?

Answer 11

A transient increase in A increases the binding of Ca to Calmodulin, altering the structure of the Ca-Calmodulin complex
The Ca-Calmodulin complex is able to activate numerous effector proteins

Question 12

How many Ca ions bond with Calmodulin?

Answer 12

4

Question 13

What are two examples of proteins activated by Ca/calmodulin?

Answer 13

Ca/Calmodulin dependent protein kinase

Nitric Oxide synthase

Question 14

G-protein coupled receptors

Answer 14

A single polypeptide consisting of 7 transmembrane a-helices

40% of drugs target these receptors

Question 15

How do agonist activate GPCRs?

Answer 15

When an agonist binds to a GPCR, it alters the protein conformation, leading to the activation of a trimeric G-protein

Question 16

Describe the G-protein cycle

Answer 16

1) Ligand binds to GPCR, which stimulates GDP-GTP exchange
2) This causes the complex to dissociate and fall apart in two pieces - Ga and GBGy (both can participate in cell signaling events)
3) The Ga has an intrinsic GTPase activity and eventuall the GTP is hydrolyzed to GDP and Pi (this process is accelerated by RGS proteins)
4) After GTP hydrolysis, the complex reassembles (Ga binds to GBGY, which once again binds to GPCR)

Question 17

Which compound of the G-protein cycle is the major signaler, and which is the minor signaler?

Answer 17

Major: Ga
Minor: GBGy

Question 18

What is the course of action for adenylate cyclase?

Answer 18

It hydrolyzes ATP to cAMP and Pi.
cAMP activates protein kinase A
PKA alters the activity of hundreds of target proteins

Question 19

How can PKA alter gene expression?

Answer 19

PKA can phosphorylate transcription factors that bind to target genes and up-regulate their expression

Question 20

What effect does Ga have on Phospholipase A2?

Answer 20

It activates PLA-2, which liberates arachadonic acid

Question 21

What is the importance of arachadonic acid?

Answer 21

It is the source of eicosinoid signaling molecules

Question 22

What is the importance of Phospholipase CB?

Answer 22

Activated Ga comes in and hydrolyzes PLCB, which cleaves PIP2 (a minor phospholipid in the membrane), producing DAG and IP3, which are important signaling molecules.

Question 23

What is the importance of GBGy?

Answer 23

Helps localize trimeric G protein to the membrane

Plays a critical role in turning off GPCR (desensitization)

Question 24

Describe the process of GPCR desensitization

Answer 24

1) Phosphorylation of GRK (recruited by GBGy)
2) Binding by B-arrestin
3) Formation of clathrin-coated pit
4) Receptor is endocytosed

Question 25

What are the two possible fates of an endocytosed GCPR?

Answer 25

1) Recycling

2) Degradation

Question 26

When can receptor desensitization occur?

Answer 26

When drugs are administered chronically

Question 27

What types of tyrosine kinases can be associated with YRKs?

Answer 27

Extrinsic or intrinsic tyrosine kinases

Question 28

What happens to Tyrosine Kinase receptors when bound to a ligand?

Answer 28

They dimerize - can either be a heterodimer or a homodimer

Question 29

What are possible ligands for Tyrosine Kinase receptors?

Answer 29

Growth factors
Differentiation factors
Cytokines

Question 30

What happens when a tyrosine kinase receptor dimerizes?

Answer 30

It leads to transphosphorylation of receptors

Question 31

What happens when dimerized tyrosine kinase receptors transphosphorylate?

Answer 31

Signaling molecules are recruited and dock on the RYKs

Question 32

What leads to different signaling cascades of RYKs?

Answer 32

The positioning of proteins near the membrane

Question 33

Describe the JAK-STAT signaling cascade

Answer 33

1) Ligand (cytokine) binding leads to phosphorylation of receptor by JAK kinase
2) This leads to the binging of a STAT protein to the phosphorylated receptor
3) The STAT protein gets phosphorylated by JAK kinase
4) This leads to the dimerization of STAT protein
5) This leads to translocation of the STAT dimer to the nucleus and transcriptional activation of panels of genes

Question 34

What are the characterizations of Ligand activated nuclear receptors?

Answer 34

Class 1

Class 2

Question 35

Class 1 nuclear receptor mechanism

Answer 35

Ligand binding induces the complex to fall apart, form a homodimer, and bind to specific DNA response elements
Once bound to DNA response elements, it binds to coactivators to induce transcription

Question 36

Class 2 nuclear receptor mechanism

Answer 36

Binds to specific DNA response elements in the absence of ligands, and is bound to corepressors
When a ligand binds, it switches form corepressors to coactivators