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Biochem > Signal Transduction > Flashcards

Signal Transduction Flashcards

1
Q

Types of signals (6)

A
  • Hormones and growth factors
  • Neurotransmitters
  • Smells
  • Taste sensations
  • Light
  • Extracellular matrix
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2
Q

How is ECM a signal? What condition does it play an important role in?

A

It is the surface on which cells attach themselves. So, physical contacts via protein to protein that are made between cells and ECM are important in cancer biology.

Cancer cells do not attach themselves to ECM as well leading to metastasis.

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3
Q

Receptors- what do they do and where are they

A

Receive signal.

Majority are at PM, some inside.

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4
Q

Signal amplification involves (3)

A

G proteins
Second messengers
Activation of kinases and phosphatases which change activity of metabolic enzyme or growth promoting enzyme

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5
Q

Cellular response is caused by _____

A

Amplification of the signal

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6
Q

2 outcomes of signal transduction pathways

A
  1. Change the activity of a metabolic enzyme or group of enzymes using kinases/phosphatases
  2. Increase/decrease gene expression
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7
Q

Receptor specificity

What happens when a signal binds?

A

When a signal binds it is by NCIs –> can cause changes in NCI

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8
Q

All receptors are _______

A

Transmembrane

  • outside to accept signal
  • have a domain that is inside for signal to be relayed
  • bind polypeptide hormones or other molecules which are not permeable to membrane
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9
Q

Amplification

A

Hormones do not have to be present in high concs to have a large effect.

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10
Q

When enzymes activate enzymes, _______

A

The number of affected molecules increases

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11
Q

What is the purpose of having a process with many steps?

A

Multiple points of regulation and ability to capture utilizable amounts of energy

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12
Q

Integration

A

Take signals coming from different directions –> pool together –> get a “net response”

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13
Q

Two hormones can:

A
  1. Work together and trigger similar types of responses

2. Oppose each other

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14
Q

Example of hormones that work together

A

Glucagon and epinephrine

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15
Q

Example of hormones that opposite other and their importance

A

Glucagon and insulin –> glucose homeostasis

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16
Q

Why is glucose homeostasis important?

A

Brain has high demand for glucose

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17
Q

Two types of signal transduction pathways to know

A
  1. G-Protein Coupled Receptors (GPCR)

2. Receptor Tyrosine Kinases

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18
Q

General characteristics of GPCR: (3)

What is the general mechanism

A
  • has multiple alpha helices that snake in and out of membrane
  • is an integral protein
  • do NOT have enzymatic activity
  • external signal binding to receptor activates an intracellular GTP-binding protein (G protein), which regulates an enzyme that generates an intracellular messenger
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19
Q

GPCR: What has enzymatic activity

A

The G Protein

NOT the receptor

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20
Q

2 Main differences between GPCR and receptor tyrosine kinases (RTKs)

A
  1. Receptor tyrosine kinases have enzymatic activity, GPCR do not. Therefore, the receptor can phosphorylate other proteins.
  2. Receptor tyrosine kinases do not have second messengers
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21
Q

General mechanism of receptor tyrosine kinases

A

Signal binding to extracellular domain stimulates enzyme activity in intracellular domain

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22
Q

GPCR interacts with ______

A

Heterotrimeric G protein

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23
Q

Heterotrimeric G protein

A

3 subunits- alpha, beta, gamma

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24
Q

What G protein subunits are anchored in PM by covalent bonds (lipid anchor)?

Importance?

A

Alpha and gamma.

Allows alpha to dissociate from beta and gamma when GTP binds and move laterally to bind to and activate adenylate cyclase

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25
Q

Alpha subunit of G-protein important characteristics (2)

A
  1. Where GTP binds for activation

2. Has GTPase activity. Therefore, it can hydrolyze GTP to terminate its own signal

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26
Q

When GTP binds to the alpha subunit, _______

A

A GTP/GDP exchange takes place.

GDP comes off, GTP comes on

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27
Q

Inactive vs. active GPCR

A

Inactive –> has GDP bound to Galpha

Active –> has GTP bound to Galpha

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28
Q

GPCR- Step 1

A

Epinephrine or glucagon binds to GPCR –> triggers a conformational change in G protein

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29
Q

GPCR- Step 2

A

GDP comes off alpha subunit and GTP comes on

Result: G-protein is now activated.

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30
Q

GPCR- Step 3

A

Galpha dissociates from beta and gamma and moves laterally in membrane to activate adenylate cyclase.

Physical contact triggers conformational change to activate catalytic function

31
Q

GPCR- Step 4

A

AMPLIFICATION

Adenylate cyclase produces second messenger cAMP using ATP as a substrate.

32
Q

Adenylate cyclase keeps producing _____ as long as _____

A

CAMP ; Galpha is bound

33
Q

Properties of cAMP (3)

A
  • polar
  • charged
  • diffuses away from membrane
34
Q

GPCR: Step 5

A
  • AMPLIFICATION *

CAMP activates multiple protein kinase A molecules

35
Q

PKA structure and how it is activated

A

Made up of:

  • 2 catalytic subunits
  • 2 regulatory subunits
  • 4 binding sites for cAMP (2 on each regulatory subunit)

The 2 regulatory subunits typically prevent PKA from always being active through NCI. But, when 4 cAMP bind to the regulatory subunit a conformational change disrupts the NCI between the regulatory and catalytic subunits and the catalytic subunit is now active.

36
Q

GPCR- Step 6

A

Active PKA phosphorylates several enzymes to change their activity.

How? Use ATP as phosphate donor (ATP is split)

37
Q

3 ways to terminate signal in GPCR

A
  1. GTPase activity of Galpha subunit
  2. Phosphodiesterase degrades cAMP
  3. Hormone dissociates from receptor
38
Q

GTPase activity of Galpha subunit

A

Galpha hydrolyzes GTP to produce GDP

Galpha re associates with beta and gamma subunits

39
Q

Phosphodiesterase

How?

A

Degrades cAMP and terminates signal

Cyclization is cleaved –> AMP made –> can be phosphorylated to ADP –> ATP

40
Q

Caffeine affect on phosphodiesterase…result?

A

Inhibits phosphodiesterase therefore…

stops the breakdown of cAMP and HR increases

41
Q

How does hormone dissociate from a receptor

A

Tissue that makes hormone is no long receiving signal so hormone conc is diluted out and eventually hormone will come off receptor

42
Q

Cholera toxin mechanism

A

ADP-ribosylation:

Galpha subunit has Arg residue….
In the presence of ADP-ribose, cholera toxin transfer the ADP-ribose to the Arg. This is a large, covalent modification that targets Galpha in its active site

Result: Galpha cannot hydrolyze GTP so adenylate cyclase is constantly activated

43
Q

What happens when adenylate cyclase is constantly activated due to ADP-ribosylation?

A

The Galpha subunit regulates the activity of a gated ion channel in small intestine –>

When G alpha is ADP-ribosylated, the channel remains open and Na+ rushes out and H2O follows…..gives rise to symptoms associated with cholera toxin

44
Q

Glucagon (2)

A
  • Small protein

- Released by Pancreas

45
Q

Epinephrine (3)

A
  • Modified amino acid
  • beta adrenergic signaling associated with flight or fight response
  • released from adrenal medulla
46
Q

Glycogen (3)

  • is what?
  • stored in?
  • degraded by?
A
  • Large polysaccharide of glucose
  • Stored in skeletal muscle and liver to maintain glucose homeostasis during overnight fast and exercise
  • Degraded by phosphorylase a
47
Q

Muscle has receptors for:

A

Epinephrine ONLY

  • DOES NOT respond to glucagon.
48
Q

Liver has receptors for:

A

Epinephrine AND glucagon

49
Q

In the muscle, glycogen is broken down into glucose when?

What happens?

A

When epinephrine binds to receptors.

Glucose stays in the muscle and goes through glycolysis to provide energy for muscle contraction.

50
Q

In the liver, glycogen is broken down into glucose when?

What happens?

A

Either epinephrine or glucagon bind to receptors.

Glucose goes into the bloodstream to maintain glucose homeostasis –> governs metabolism

51
Q

Other second messengers in GPCR (4)

A
  1. In central nervous system, cGMP
  2. Ca+
  3. Inositol 1,4,5-triphosphate (IP3)
  4. Diacylglycerol (DAG)
52
Q

Signaling through phosphotidylinositol

A

Phosphotidylinositol is present in low conc in the PM and can be cleaved to yield DAG and IP3 which are second messengers in signal transduction

53
Q

Mechanism of signaling using phosphotidylinositol

A
  1. Phosphotidylinositol phosphorylated to become PIP2
  2. Phospholipase C breaks down by cleaving the P and inositol
  3. Left with DAG and IP3

DAG –> stays in membrane
IP3 –> diffuses away (charged)

54
Q

GPCR-PI Cascade Mechanism

  1. IP3 diffuses away from membrane and binds to….
A
  1. IP3 binds to IP3 receptor on the smooth endoplasmic reticulum membrane
  2. IP3 receptor is a gated ion channel, so when IP3 binds the channel opens –> Ca2+ comes out and into cytoplasm
  3. Protein kinase C activated by DAG and Ca2+ binding
55
Q

Protein kinase C activation keys

A

For maximal activity, PKC requires BOTH Ca2+ and DAG.

DAG can work by itself, but activity not as high.

56
Q

PKC important in?

What hormones work by this cascade?

A

Growth control

Vasopressin and oxytocin

57
Q

Epidermal Growth Factor (EGF) receptor structure

A

Extracellular EGF binding domain –> transmembrane helix –> intracellular kinase domain –> tyrosine rich C terminal tail

2 monomers of receptor

58
Q

PKA and PKC typically phosphorylate ___ and ____ for metabolic control

A

Tyr and Ser residues

59
Q

What happens when EGF bind to extracellular domain of receptor

A

The receptors dimerize. –> The two monomer subunits phosphorylate each other and activate receptor.

60
Q

Mechanism of EGF

A
  1. EGF binds to receptor
  2. Dimerization of two monomer subunits –> phosphorylate each other –> activation of tyrosine kinase activity of the receptor (phosphates serve as binding sites for other proteins)
  3. Grb-2 binds to receptor
  4. Grb-2 interacts with Sos
  5. Sos triggers exchange of GDP for GTP on Ras to activate Ras
  6. Ras relays signal to interior of the cell
61
Q

Ras

A
  • Similar to Galpha
  • Small protein, NOT a second messenger
  • Has 2 amino acid residues that bind GTP
62
Q

Important amino acid residues in Ras and consequences of mutations

A

Glycine 12 and Glutamine 61

Mutations in these residues are common in tumors. The mutations affect the ability of Ras to hydrolyze GTP therefore Ras always stays active –> entire growth signal continually keeps going

63
Q

Ras relays signal to interior of the cell

A

Ras –> Raf–> MEK –> Erk1 or Erk2 –> goes on to affect many other protein for growth

In this cascade, kinases activate other kinases

64
Q

Other example of RTK

A

Insulin Receptor

65
Q

Insulin receptor structure

A
  • A dimer
  • alpha subunits (extracellular) and beta subunits (intracellular) connected by 2 S-S bonds
  • Also a S-S bond the connects the alpha subunits
66
Q

Binding of insulin to ____ subunit ______

A

To alpha subunit activates the beta subunit that contains the kinase activity

67
Q

Mechanism of Insulin Receptor (RTK)

  1. Insulin binds to alpha subunit and….
A
  1. And activates the beta subunit. The beta subunit phosphorylate each other and the phosphates serves are binding sites for other proteins
  2. Insulin receptor substrate 1 (IRS-1) binds to receptor
  3. Receptor phosphorylates IRS-1 at tyrosine sites and those phosphates serve as binding sites
  4. PI-3-Kinase interacts with IRS-1
  5. PI-3-Kinase phosphorylates PIP2 –> PIP3 using ATP. PIP3 remains in the membrane and serves as a docking site for PDK-1
  6. PDK-1 binds to PIP3 and becomes activate
  7. PDK-1 phosphorylates Akt (protein kinase B) to activate it
68
Q

Activated Akt (protein kinase B) leads to….

A

Many steps that lead to the recruitment of glucose transporters to the plasma membrane

69
Q

Insulin sensitive tissues

Why?

A

Skeletal muscle and adipose tissue

Their transporters are low Km so when glucose concs rise in the blood they are already saturated –> insulin signal transporters in the cell to move to the membrane

70
Q

Mechanism of recruiting glucose transporters to membrane of skeletal muscle and adipose tissue

A
  1. Akt triggers many proteins that cause the movement of vesicles containing glucose transporters (GLUT4)
71
Q

GLUT4

Where?
Km?

A
  • Specific to skeletal muscle and adipose tissue

- Low Km

72
Q

What would happen if additional transporters were not brought to the membrane?

A

Because the transporters have low Km, they are working at saturation especially when glucose levels rise after a meal. Without the additional transporters, blood glucose levels would remain higher for longer

73
Q

Insulin signal termination

A

Requires protein phosphatases and lipid phosphatases

Biochem (15 decks)

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