Lecture 15. Receptor Enzymes

Question 1

What are the classes of receptors?

Answer 1

Receptors with intrinsic enzyme activity
Receptors linked to protein kinases
Receptors coupled to target proteins via a G protein
Intracellular receptors
Receptors that are ion channels

Question 2

What is the prototype for receptors that are enzymes?

Answer 2

Insulin receptor (IR)

Question 3

What is the normal blood glucose level?

Answer 3

~4.5 mM

Question 4

What does insulin do?

Answer 4

Lowers blood sugar levels

Question 5

What does glucagon, epinephrine and cortisol do?

Answer 5

Raises blood sugar levels

Question 6

What do α cells secrete?

Answer 6

Glucagon

Question 7

What do β cells secrete?

Answer 7

Insulin

Question 8

What do δ cells secrete?

Answer 8

Somatostatin

Question 9

Following translation, what do the receptor subunits do?

Answer 9

1. Enter the ER (endoplasmic reticulum) membrane,
   secretory vesicle
2. Associate into dimers,
3. and are exported to the cell surface, via the Golgi complex
4. During intracellular transport, the proteins are processed by cleavage, each into an α and a β subunit.
5. At the plasma membrane, they are displayed as trans-membrane proteins

Question 10

Where does insulin signalling start?

Answer 10

At the plasma membrane: insulin binding stimulates an allosteric change in IR, bringing the cytosolic domains close, allowing activation

Question 11

What is a first messenger/primary messenger/ligand?

Answer 11

An extracellular substance (for examples, the hormone epinephrine or the neurotransmitter serotonin) that binds to a cell-surface receptor and initiates signal transduction that results in a change in intracellular activity

Question 12

What is a receptor?

Answer 12

A protein that binds and responds to the first messenger
Receptors may be either displayed at the cell-surface (e.g. IR, EGFR, GPCRs) or may be intracellular

Question 13

What does activated IR phosphorylate activate?

Answer 13

Insulin receptor substrate-1 (IRS-1)

Question 14

What binds to activated IRS-1?

Answer 14

Adaptor molecules Grb2 and Sos

Question 15

What does Sos convert inactive (GDP-bound) Ras to?

Answer 15

Active (GTP-bound) Ras

Question 16

What does activated Ras recruit?

Answer 16

Raf kinase to the membrane and activates its protein kinase activity. RAF phosphorylates and activates MEK kinase. MEK phosphorylates and activates mitogen- activated protein kinase (MAPK)

Question 17

What does IRS-1 also recruit and activate?

Answer 17

Phosphoinositide 3-kinase (PI-3K) to the cytosolic face of the plasma membrane

Question 18

What does PI-3K phosphorylate do?

Answer 18

The membrane lipid phosphotidylinositol 4,5 bisphosphate (PIP₂) to produce phosphotidylinositol 3,4,5 trisphosphate (PIP₃)

Question 19

What is a secondary messenger?

Answer 19

A small metabolically unique molecule, not a protein, whose concentrations can change rapidly.
Second messengers relay signals from receptors to target molecules in the cytoplasm or nucleus

Question 20

What does PIP₃ recruit?

Answer 20

PDK1 (PIP3-dependent protein kinase)

Question 21

What does insulin do as a growth factor?

Answer 21

Phosphorylation of IRS-1 amplifies the signal
Adaptors recruit and activate Ras
Signal transduction via an amplifying MAPK cascade
Response: Gene expression changes

Question 22

What does insulin do as a glucose regulator?

Answer 22

Phosphorylation of IRS-1 amplifies the signal
Signal propagation and amplification via conversion of membrane lipids
Amplification via a lipid dependent kinase and activation of PKB
Responses: Upregulation of glucose entry into cells and upregulation of glycogen production

Question 23

Which cells regard insulin as a growth factor?

Answer 23

Fibroblasts are the best example

Question 24

What is the cellular response to insulin within minutes?

Answer 24

Increased uptake of glucose into muscle cells and adipocytes
Altered glucose metabolism by modulation of enzyme activities

Question 25

What is the cellular response to insulin within hours?

Answer 25

Increased expression of liver enzymes that synthesise glycogen
Increased expression of adipocyte enzymes that synthesise triacylglycerols
Increased expression of genes involved in mitogenesis in some cell lines