Lecture 23: Catalytic Receptors

Question 1

Autonomic Transmitters:
N-cholinergic receptors

Answer 1

-N-cholinergic receptors are ion channels

they Signal through membrane potential

Question 2

Autonomic Transmitters:
b-adrenergic receptors

Answer 2

• b-adrenergic receptors are GPCR

they Signal through second messengers e.g. cAMP

Question 3

Glucose Regulation
- Skeletal muscle;

Answer 3

Skeletal muscle; adrenaline causes glycogen break down.

Question 4

What is Islets of Langerhans?

What does it do? blood? loop? pathway?

Answer 4

1. Insulin released from b-cells in the islets of Langerhans.
2. Increased blood glucose causes insulin release
3. Insulin causes blood glucose to fall
4. Negative feedback loop
5. Islet cells are receptor, afferent pathway and central processor.
6. Insulin is the efferent pathway

Question 5

Release of Insulin STEPS? (9)

Answer 5

1. Glucose enters istle cells through *GLUT2 glucose transporter
2. Increased blood glucose→ more glucose enters cell
3. More glucose→ entry more ATP production
4. ATP binds to and CLOSES *KATP channels
5. Less K+ efflux depolarizes the cell
6. Depolarization open Ca2+ channels
7. Calcium binds to SYNAPTOTAGMIN (just like in nerves)
8. SNARE proteins change conformation trigger exocytose of vesicles
9. Insulin released (just like neurotransmitter release

Question 6

Insulin Release Glucagon: 3

Answer 6

1. Glucagon acting through Gs also stimulates insulin
2. Gs activates adenylate cyclase, produces cAMP, turns on PKA that phosphorylates proteins.
3. Adrenaline via a2-receptors acting on Gi inhibits insulin release by suppressing PKA

Question 7

What does Insulin do (Muscle): 8

Answer 7

1. Increased glucose uptake into skeletal muscle cells
2. Insulin sensitive GLUT4 glucose transporters inserted in cell membrane
3. Cells have vesicles with GLUT4 in the vesicle membrane
4. Binding of vesicles to the cell membrane adds glucose transporters to the cell membrane
5. Turns on synthesis of glycogen (stores glucose)
6. Increased production of key glycolytic enzymes
7. Turns on protein production in general
8. Turns off use of fat as energy, store more fat

Question 8

How does Insulin Receptor? =4

Answer 8

1. Insulin receptor is a RECEPTOR TYROSINE KINASE.
2. Tyrosine kinases are a common group of catalytic receptors.
3. Receptor tyrosine kinases
4. Tyrosine kinase associate receptors

Question 9

What does a KINASE USE?

Answer 9

A kinase used ATP to phosphorylate something

Question 10

What does a Phosphatase do?

Answer 10

A phosphatase unphosphorylates something

Question 11

Protein kinases come in two groups:

Answer 11

1. Serine/threonine kinases e.g. myosin light chain kinase
2. Tyrosine kinases e.g. Insulin receptor

Question 12

Receptor tyrosine kinases are?

In Insulin receptor?

Answer 12

• Receptor tyrosine kinases: are them selves enzymes which are turned on by their ligand
• Insulin receptor, platelet derived growth factor, nerve growth factor, many growth factor receptors.

Question 13

Tyrosine kinase associated receptors have:

eg.

Answer 13

Tyrosine kinase associated receptors have the kinase as a separate subunit that binds the receptor

• Growth hormone and erythropoietin (EPO) receptors

Question 14

Five known types of catalytic receptor:

Answer 14

1. Tyrosine kinases
2. Receptor serine/threonine kinase
3. Receptor tyrosine phosphotases

4.Receptor guanylate cyclase

Question 15

Tyrosine kinases = 3

Answer 15

1. Receptor tyrosine kinase
2. Tyrosine kinase associated receptors
3. Most common

Question 16

Receptor serine/threonine kinase (rare)

Answer 16

• RARE

-Phosphorylate target proteins on serine or threonine

Question 17

Receptor tyrosine phosphotases (very rare)

Answer 17

• VERY RARE
• Dephosphorylate target protein on a tyrosine

Question 18

Receptor guanylate cyclase

(guanylyl cyclase, guanyl cyclase)

Answer 18

• (guanylyl cyclase, guanyl cyclase)
• Activated by NO= nitric oxide makes cGMP from GTP
• Similar to adenylate cyclase

Question 19

Effects of Insulin

How many things can one receptor do?

Answer 19

Lots!

Needs more simplification

SLIDE 16

Question 20

Cellular Actions of Insulin: 5

Answer 20

1. Very very complex, many different pathways and interacting signal pathways get activated.
2. No small molecule second messengers but a great many protein kinases
3. Much of the signalling is through protein phosphorylation
4. Modifies existing proteins
5. And modified DNA transcription

Question 21

Insulin Effect: 2

Answer 21

1. Autophosphorylation
2. Protein Kinase B

Question 22

Protein Kinase B Pathway: 5

Answer 22

1. Insulin binding causes insulin receptors to autophosphorylate, i.e. they phosphorylate them selves.
2. A collection of proteins collectively called INSULIN RESPONSE SUBSTRATES (IRS) are phosphorylated.
3. Through intermediate steps that phosphorylates the membrane lipid phosphatidylinositol to PHOSPHATIDYLINOSITOL-3-PHOSPHATE (do not confuse with INOSITOL TRIPHOSPHATE).
4. Activates (through more steps) PROTEIN KINASE B (PKB) also called Akt.
5. PKB turns on glycogen synthesis and adds **GLUT 4 to the cell membrane

Question 23

Insulin and Gen Expression (10)

Answer 23

1. Ligand binding causes receptor dimerization.
2. the activated RTK phosphorylates itself.
3. GRB2, an SH2-containing protein, recognises the phosphotyrosine residues.
4. the binding GRB2 recruits SOS.
5. SOS activates Ras by causing GTP to replace GDP on Ras.
6. the activated GTP-Ras recruits Raf-1 and activates it.
7. Raf-1 phosphorylates and activates MEK.
8. MEK phosphorylates and activates MAPK.
9. MAPK works as an important effector molecule by phosphorylating many cellular proteins.
10. MAPK translocates to the nucleus where it phosphorylates a transcription factor.

Question 24

MAPK Pathway: 6

Answer 24

1. Insulin binding causes insulin receptors to autophosphorylate, i.e. they phosphorylate them selves.
2. Through many intermediate steps mitogen activated protein kinase (MAPK) gets activated.
3. MAPK translocated to the cell nucleolus
4. Phosphorylates transcription factors and changes gene expression
5. General increase in protein synthesis
6. Specific increase in key glycolysis pathway enzymes e.g. Hexokinase

Question 25

Insulin Signalling: 7

Answer 25

1. Two major pathways (an over simplification)
2. Signals through PI-3P and PKB, activated glycogen synthesis and translocates GLUT 4 glucose transporters to the cell membrane
3. Signals though MAPK, change gene expression.
4. Changes in gene expression alter the amount of an enzyme in a cell not just the activity of previously present enzymes.
5. Many steps means a lot of signal amplification
6. But also slow response time
7. Changes in gene expression slow to turn on but long lasting

Question 26

Summary 6

Answer 26

1. Entry of glucose into b-cells closes ATP sensitive K+ channels, depolarizes the cells and causes exocytosis of insulin.
2. Insulin acts on skeletal muscle to increase glucose uptake, glycogen synthesis and change gene expression
3. Insulin receptors are tyrosine kinases
4. 5 types of catalytic receptor
5. Insulin receptor leads to activation of PKB that causes increased glucose uptake and glycogen synthesis
6. Also activates MAPK that changes gene expression