Lecture 8: Receptor Enzymes Flashcards
Monday 27th January 2025
How are some receptors also enzymes?
Because when a ligand binds to these receptors, enzyme activity is activated. For example, the insulin receptor
The actions of which hormones are required to regulate blood glucose levels?
- Insulin (pancreatic): lowers blood sugar levels
- Glucagon (pancreatic): raises blood sugar levels
- Epinephrine (adrenal): raises blood sugar levels
- Cortisol (adrenal): raises blood sugar levels
Where are acini cells located?
At the end of ducts
What functions do acinar cells have?
Digestive functions
What is located between the acinar cells?
The islets of langerhans
Is the insulin receptor made from a single protein, from a single gene?
Yes
Describe what happens to the insulin receptor subunits after translation?
- 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
What activates the insulin receptor at the cell surface?
The binding of insulin
Summarise what happens when insulin binds to the insulin receptor
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.
What is a First messenger/primary messenger/ligand?
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
What is a receptor?
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).
Describe the first step of insulin signalling
- 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.
)
Describe the second step of insulin signalling
- IRS-1 is actiavted and can be consequently captured by Grb2, which is associated with Sos.
(Sos is a guanine nucleotide exchange factor (GEF)
)
What is the 3rd step of insulin signalling?
- 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.
)
What is the 4th step of insulin signalling?
- 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.)
What is the final step of insulin signalling?
- Activated ERK migrates to the nucleus and acts as a transcription factor (required for cell division).
-
Hence, what can be concluded about insulin?
That it is a growth factor that stimulates growth
Describe the first step of glucose regulation
- IRS-1 is bi-functional.
It also recruits and activates phosphoinositide 3-kinase (PI-3K) to the cytosolic face of the plasma membrane
-
Describe the second step of glucose regulation
- PI-3K phosphorylates the membrane lipid PIP2 to PIP3.
- PIP 3 is a second messenger
What is a second messenger?
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.
What is the 3rd step of glucose regulation?
- PIP3 recruits PDK1 (PIP3-dependent protein kinase).
- PDK1 activates protein kinase B
Is it true that insulin is both a growth factor and a blood glucose regulator?
Yes
What is the overall response when insulin binds to the insulin receptor?
The gene expression changes
What is the overall response in glucose regulation?
Upregulation of glucose entry into cells and upregulation of glycogen production
What allows insulin to be both a growth factor and a glucose regulator?
The bi-functionality of IRS-1
Why does insulin act as both a growth factor and a glucose regulator?
Because there’s not much point of growing if there’s no food supply
Which cells regard insulin as a growth factor?
Fibroblasts
How is the fast Ras-independent pathway terminated?
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.
What causes type I diabetes?
Deficiency in insulin production
What causes type II diabetes?
Failure to respond to insulin
In muscle and adipose tissues, what stimulates the movement of the glucose transporter GLUT4 from internal membrane vesicles to the PM, increasing glucose uptake?
activated PKB
What mediates the conversion of excess glucose to glycogen (in the liver/muscles) and to triacylglycerols (in adipose tissue)?
PKB
What are characteristic symptoms of both types of diabetes?
excessive thirst
frequent urination (polyuria)
excretion of large amounts of glucose in the urine (glucosuria)
Do high blood glucose levels desensitise the ability of the insulin receptor to respond to insulin?
Yes
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