Cell Signaling

Question 1

What are the 3 stages of cell signaling?

Answer 1

1. Reception
(receptor binds to ligands)

2. Transduction
(receptor protein changes and activates intracellular molecs aka 2nd messengers)

3. Cell Response

(cell responds to signal)

Question 2

What is another name for G-protein coupled receptors?

Answer 2

7-pass transmembrane receptors

Question 3

What do the alpha and gamma subunits do for GPCRs?

Answer 3

anchored to cell membrane and keep G-protein next to the receptor

Question 4

What does a GPCR bind to when it’s inactive?

Answer 4

GDP

Question 5

What happens to GPCR when its alpha subunit is bound to GTP?

Answer 5

alpha subunit seperates from beta and gamma subunits and alpha subunit is then free to interact with other proteins

Question 6

Answer 6

Gq

Question 7

• Bound to adenylate cyclase but inhibits it, causing (-) feedback to Gs

**negative feedback is important with helping to inactivate cells

Answer 7

Gi

Question 8

• stimulates adenylate cyclase
• Activated adenylate cyclase takes ATP and removes 2 phosphate molecs transforming it into cAMP
• regulated subunit then dissociates from catalytic subunit

Answer 8

Gs

Question 9

Single pass transmembrane proteins (meaning they have 1 transmembrane segment and intracellular end has intrinsic cellular activity)

Answer 9

Enzyme coupled receptor

Question 10

What are the 2 parts of enzyme coupled receptors?

Answer 10

1. Receptor
2. Enzyme (protein kinase that phosphorylates receptor)

Question 11

What are the 3 main types of ECRs?

Answer 11

1. Tyrosine Kinase associated Receptor
2. Receptor Tyrosine Kinase
3. Receptor Ser/Thr Kinase

Question 12

• most common enzyme coupled receptor
• has many subfams
• can’t phosphorylate its own Tyr side chains

Answer 12

receptor tyrosine kinases

Question 13

• Works similarly to receptor Tyr Kinase
• no intrinsic enzyme activity
• receptor binds to ligand
• Cytoplasmic Tyr Kin
• Phosphorylates target proteins to relay signal

Answer 13

Tyr Kinase associated Receptor

Question 15

Type ii - Ser/Thr kinase domains receptor phosphorylates and activates type i receptor which recruits and phosphorylates various target proteins to relay signal

Answer 15

Receptor Ser/Thr Kinase

Question 16

Answer 16

Ion Channel Receptor

Question 17

Activates a receptor that has access to 2 signal pathways. However, the biased ligand only activates 1 of the pathways

Answer 17

Biased ligands

Question 18

Discuss the concept of FM (Frequency Modulated) hormone signaling and give an example.

Answer 18

Fidelity of FM radio is better than that of an AM radio. It is the frequency (number of spikes/sec) is the determinant (critical variable)

Low freq pulses on the left cause little change in calmodulin kinase activity compared with high freq changes on the right.

Question 19

Describe the role of macromolecular complexes in cell signaling with examples.

Answer 19

A-kinase Anchor Protein (AKAP)

Pyruvate dehydrogenase complex

Causes many biochemical events that leads to cell activation and effector responses

Question 20

Describe the importance of location in cell signaling and mechanisms involved in creating signaling domains / “signalosomes”.

Answer 20

This makes sure that signaling molecules/ enzymes encounter the right substrates at the right place at the right time

Improves efficiency by boosting local concentration of signaling and their targets

Ex: B1AR (distributed across entire cell surface, including T tubules) and B2AR (distributed only on T tubles in muscle cells and are part of the mech involving calcium) are differentially distributed across the membrane instead of just in the T tubules. This leads to cardiotoxicity/ programmed cell death

In a failing heart, B2AR location is disrupted and instead distributed

Question 21

Give examples of the importance of membrane fluidity in cell signaling.

Answer 21

If you drink a lot of alcohol (like an alcoholic) alcohol is inserted into the membrane. This increases membrane fluidity. As a result, this messes with the way cells interact and signal each other. Target cells are able to recognize this and changes membrane lipid composition to adjust the problem.

Cholesterol (blood lipid): affects ability of proteins embedded in the membrane (including receptors) to change their configuration (think denaturing protein structure). Like trimeric G protein activation. Cholesterol affects ability to reconfigure properly

Woodchucks: In order to get through hibernation, cold body temp require them to adjust their membrane lipids to be made seasonally to maintain fluidity. This can be done by increasing unsaturated FA chain or increase proportion of short chain FA due to reduced Vander Waals interactions

Question 22

Define the role of hormone surface receptor regulation in determining hormone sensitivity and responsiveness.

Answer 22

****Not all receptors available have to be bound in order to achieve maximal response

LDL receptor story:

LDL travels in blood and bound to LDL receptors on surface of the protein. Once bound, the whole complex is internalized. Delivering LDL to the cell and removing LDL from the surface. When the cell has all the intracellular LDL, it doesn’t take much up anymore due to reduced number of plasma membrane receptors. This is bc LDL has become relocated in the interior so there aren’t anymore on the surface. But when cell needs LDL, more appears on the surface (negative feedback)

Question 23

Define homologous receptor regulation, its physiologic significance and the mechanisms proposed to explain the process.

Answer 23

Hormones are regulating their own receptor (Ex: epinephrine or insulin)

Internalization

**there is a reciprocol relationship between hormone concentration and receptor function

Question 24

Define heterologous receptor regulation.

Answer 24

• 1 hormone is regulating receptors for a different hormone
• Menstrual cycle

Question 25

Define the enzymes involved in synthesis and degradation of cyclic-AMP.

Answer 25

Synthesis: adenylyl cyclase Degradation: cyclic AMP phosphodiesterase

Question 26

Which of the following statements best describes receptor tyrosine kinases (RTKs)? RTKs:

Answer 26

## Footnote autophosphorylate themselves.

Question 27

Phosphorylation of tyrosine amino acid residues of the surface receptor protein in the signal pathway for growth factors such as epidermal growth factor or insulin (1)\_\_\_\_\_\_\_ ; while phosphorylation of serine or threonine amino acids on that receptor (2) _______ the signal pathway.

Answer 27

Activates, Inactivates

Question 28

Define the enzymes involved in synthesis and degradation of cyclic-AMP

Answer 28

Synthesis: adenylyl cyclase Degradation: cyclic AMP phosphodiesterase

Question 29

What is involved in the cAMP signaling cascade for cell differentiation, proliferation, etc?

Answer 29

1. GPCR is activated by change when the appropriate signal is bound (Heterotrimeric which is made of alpha, beta, and gamma subunits), found at cell surface and is needed for cell surface hormone signaling pathways) 2. Gs complex is now activated 3. cAMP is then activated by Gs 4. cAMP causes inhibitory unit to fall off of PKA so PKA can phosphorylate and be active

Question 30

What does PKA phosphorylate to (most often) turn off receptors?

Answer 30

PKA phosphorylates either serine or threonine 99% (1% is Tyrosine)

Question 31

What are the 3 types of signaling molec categories?

Answer 31

1. Hydrophilic - e..g amines (epinephrine, adrenaline in ANS), peptides (Signaling molecs in brain), proteins (insulin) 2. Hydrophobic - Steroids, Thyroid hormones 3. Gases

Question 32

How do surface acting hormones do their signaling?

Answer 32

1. There needs to be a specific external signal for cell to respond to **(HORMONE)** (in radio: specific radio waves) 2. Cell recognizes signal via a receptor that allows the signaling molec to bind (in radio, this is what recognizes the sound waves) 3. The bound hormone now must be translated into a recognizable signal via **transducer (G-protein)** 4. **Amplification (Adenylate Cyclase)** since now we understand the signal so, we wanna make it big enough to have an actual effect in the body. This is accomplished by **2nd messenger (e.g. cAMP)**

Question 33

What does it look like when the receptor itself is an ion channel?

Answer 33

- Ligand/hormone binds directly to an ion channel and binding causes the channel to either open or close (e.g. Ach) - Think about Ach, excitable membranes, nerve signal transmission at synapses between nerves; and between nerves and skeletal muscles (causing muscle contraction)

Question 34

What are the 4 types of surface receptor mechanisms?

Answer 34

1. receptor itself is an ion channel 2. receptor itself can be an enzyme 3. GPCR 4. Extracellular matrix through connection w the cytoskeleton

Question 35

What is cAMP's key action?

Answer 35

Activate PKA by causing the inhibitory regulatory subunit to fall off

Question 36

What's Ach's job?

Answer 36

- major neurotransmitter in the Central and Autonomic Nervous Systems (CNS / ANS) - major role is to open sodium channels in the membrane, the end result of which is membrane depolarization. This causes events such as transmission of electrical signals at synapses

Question 37

What are the 3 parts of the G-protein cAMP signaling cascade?

Answer 37

1. receptor (GPRCR) 2. G-protein (trimeric w alpha, beta, and gamma subunit) in this case, Gs to stimulate adenylyl cyclase 3. embedded in the membrane is adenylyl cyclase (key enzyme)

Question 38

What does the trimeric G-protein cycle look like?

Answer 38

Question 39

What does Gs do?

Answer 39

activates adenylyl cyclase; activates Ca2+ channels

Question 40

What does Gi do?

Answer 40

inhibits adenylyl cyclase

Question 41

What does Gq do?

Answer 41

activates phospholipase C-beta

Question 42

How does Tyr phosphorylation have a special place in regulatary pathways?

Answer 42

Special place involved w normal cell proliferation and growth and cancer

Question 43

What is CREB

Answer 43

cAMP response element binding protein

Question 44

What does the CREB steps look like for creating new machinery?

Answer 44

Note that the cell is creating new or destroying current signal machinery! It is NOT altering the activity of existing machinery