Lecture 8: Receptor Enzymes

Question 1

How are some receptors also enzymes?

Answer 1

• Because when a ligand binds to these receptors, enzyme activity is activated.
• For example, the insulin receptor

Question 2

The actions of which hormones are required to regulate blood glucose levels?

Answer 2

• Insulin (pancreatic): lowers blood sugar levels
• Glucagon (pancreatic): raises blood sugar levels
• Epinephrine (adrenal): raises blood sugar levels
• Cortisol (adrenal): raises blood sugar levels

Question 3

Where are acini cells located?

Answer 3

At the end of ducts

Question 4

What functions do acinar cells have?

Answer 4

Digestive functions

Question 5

What is located between the acinar cells?

Answer 5

The islets of langerhans

Question 6

Is the insulin receptor made from a single protein, from a single gene?

Answer 6

Yes

Question 7

Describe what happens to the insulin receptor subunits after translation?

Answer 7

• Translation occurs and individual subunits are inserted into the Endoplasmic reticulum.
• The subunits form dimers and are transferred to the Golgi apparatus
• During intracellular transport, the proteins are processed by cleavage, each into an α and a β subunit.
• At the plasma membrane, they are displayed as trans-membrane proteins

Question 8

What activates the insulin receptor at the cell surface?

Answer 8

The binding of insulin

Question 9

Summarise what happens when insulin binds to the insulin receptor

Answer 9

• Insulin binding confers shape change in the insulin receptor.
• This brings the 2 cytosolic domains in close proximity to each other.
• Trans auto-phosphorylation occurs and the insulin receptor becomes activated and can consequently phosphorylate other proteins.

Question 10

What is a First messenger/primary messenger/ligand?

Answer 10

An extracellular substance (for example, 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 11

What is a receptor?

Answer 11

• 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 (see later).

Question 12

Describe the first step of insulin signalling

Answer 12

• Activated IR phosphorylates and activates the insulin receptor substrate-1 (IRS-1)

(Biological significance: the signal has been transduced from the extracellular side of the plasma membrane to the intracellular side of the membrane and has been transferred to a soluble protein in the cytosol.)

Question 13

Describe the second step of insulin signalling

Answer 13

• IRS-1 is activated and can be consequently captured by Grb2, which is associated with Sos.

(Sos is a guanine nucleotide exchange factor (GEF)).

Question 14

What is the 3rd step of insulin signalling?

Answer 14

• Sos can capture Ras (which has a lipid anchor).
• Sos then replaces GDP with GTP to form activated Ras.
• (Biological significance: the signal has been transduced from the extracellular side of the plasma membrane to the intracellular side of the membrane and has been transferred to the G protein Ras, activating Ras in the process.)

Question 15

What is the 4th step of insulin signalling?

Answer 15

• Activated Ras recruits and activates Raf (a kinase that recruits and activates Mek).
• MEK phosphorylates and activates mitogen-activated protein kinase (MAPK). (amplification)
• (Biological significance: the signal has been transduced from the cytosolic face of the plasma membrane and amplified across the cytosol through a MAPK cascade.)

Question 16

What is the final step of insulin signalling?

Answer 16

• Activated ERK migrates to the nucleus and acts as a transcription factor (required for cell division).

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Question 17

Hence, what can be concluded about insulin?

Answer 17

That it is a growth factor that stimulates growth

Question 18

Describe the first step of glucose regulation

Answer 18

• IRS-1 is bi-functional.
  It also recruits and activates phosphoinositide 3-kinase (PI-3K) to the cytosolic face of the plasma membrane

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Question 19

Describe the second step of glucose regulation

Answer 19

• PI-3K phosphorylates the membrane lipid PIP2 to PIP3.
• PIP 3 is a second messenger

Question 20

What is a second messenger?

Answer 20

• 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 21

What is the 3rd step of glucose regulation?

Answer 21

• PIP3 recruits PDK1 (PIP3-dependent protein kinase).
• PDK1 activates protein kinase B

Question 22

Is it true that insulin is both a growth factor and a blood glucose regulator?

Answer 22

Yes

Question 23

What is the overall response when insulin binds to the insulin receptor?

Answer 23

The gene expression changes

Question 24

Insulin, via its receptor and shared adaptor proteins, can activate the Ras/MAPK pathway, leading to gene expression changes and cell cycle entry — just like classic growth factors such as EGF.

Answer 24

Insulin, via its receptor and shared adaptor proteins, can activate the Ras/MAPK pathway, leading to gene expression changes and cell cycle entry — just like classic growth factors such as EGF.

Question 25

What is the overall response in glucose regulation?

Answer 25

Upregulation of glucose entry into cells and upregulation of glycogen production

Question 26

What allows insulin to be both a growth factor and a glucose regulator?

Answer 26

The bi-functionality of IRS-1

Question 27

Why does insulin act as both a growth factor and a glucose regulator?

Answer 27

Because there's not much point of growing if there's no food supply

Question 28

Which cells regard insulin as a growth factor?

Answer 28

Fibroblasts

Question 29

How is the fast Ras-independent pathway terminated?

Answer 29

- A PIP3-specific phosphatase (PTEN) removes the phosphate at the 3 position of PIP3 to convert it into PIP2. - PDKI and PKB can no longer be recruited to the plasma membrane, shutting off signalling through PKB.

Question 30

What causes type I diabetes?

Answer 30

Deficiency in insulin production

Question 31

What causes type II diabetes?

Answer 31

Failure to respond to insulin

Question 32

In muscle and adipose tissues, what stimulates the movement of the glucose transporter GLUT4 from internal membrane vesicles to the plasma membrane, increasing glucose uptake?

Answer 32

activated PKB

Question 33

What mediates the conversion of excess glucose to glycogen (in the liver/muscles) and to triacylglycerols (in adipose tissue)?

Answer 33

PKB

Question 34

What are characteristic symptoms of both types of diabetes?

Answer 34

- excessive thirst - frequent urination (polyuria) - excretion of large amounts of glucose in the urine (glucosuria)

Question 35

Do high blood glucose levels desensitise the ability of the insulin receptor to respond to insulin?

Answer 35

Yes

Question 36

Trial

Question 37

Insulin and EGF

Answer 37

- This slide illustrates that insulin functions not only as a metabolic hormone but also as a growth factor. - It does this by activating a signalling pathway that is also used by classical growth factors like EGF (epidermal growth factor). - When insulin binds to its receptor (IR), it triggers phosphorylation events that recruit adaptor proteins such as Grb2 and Sos—these are the same adaptors involved in EGF receptor (EGFR) signaling. - This leads to the activation of the Ras protein, which initiates the MAPK/ERK signaling cascade (Raf → MEK → ERK). - Once activated, ERK translocates into the nucleus where it alters gene expression. - This includes the activation of approximately 100 insulin-responsive genes and the expression of cyclins and CDKs that are essential for cell division. - Because insulin activates this growth-promoting pathway, it is considered a growth factor in addition to its role in regulating glucose metabolism.

Question 38

What 2 pathways does the insulin receptor signal using?

Answer 38

- The Ras independent pathway, where metabolism becomes altered. - The Ras dependent pathway, where growth signals are activated.

Question 39

Growth and glucose metabolism can be co-ordinated because there is a common intermediate. What is the common intermediate?

Answer 39

PI3K (phosphoinositide 3-kinase) or Akt (also called Protein Kinase B).

Question 40

What happens when the glucose transporter, GLUT 4, is moved from internal membrane vesicles to the plasma membrane?

Answer 40

The uptake of glucose is increased

Question 41

Does PKB mediate the conversion of excess glucose to glycogen (in the liver/muscles) and to triacylglycerols (in adipose tissue)?

Answer 41

yes

Question 42

The adaptors Grb2 and Sos are common to both EGF (epidermal growth factor) and insulin signalling, so activation of EGFR (epidermal growth factor receptor) and IR recruits the same MAPK cascade ... which means the same genes are modulated in the downstream response.

Answer 42

The adaptors Grb2 and Sos are common to both EGF (epidermal growth factor) and insulin signalling, so activation of EGFR (epidermal growth factor receptor) and IR recruits the same MAPK cascade ... which means the same genes are modulated in the downstream response.