Lecture 8 Flashcards
Receptor enzymes
What are receptor enzymes?
Receptor enzymes are cell surface receptors that have intrinsic enzyme activity or are directly linked to enzymes. Ligand binding activates the enzymatic function.
What are the five classes of receptors?
- Receptors with intrinsic enzyme activity (e.g., insulin receptor).
- Receptors linked to protein kinases.
- Receptors coupled to G proteins.
- Intracellular receptors.
- Ion channel receptors.
What is the structure of the insulin receptor (IR)?
The IR is a transmembrane protein with:
- α subunits: Extracellular, bind insulin.
- β subunits: Intracellular, have kinase activity.
Made as a single protein, cleaved into α and β subunits during intracellular transport.
How is the insulin receptor activated?
Insulin binding induces a conformational change, bringing cytosolic domains close together and activating intrinsic kinase activity via autophosphorylation of tyrosine residues on β subunits.
What is the significance of insulin receptor activation?
The signal is transduced across the plasma membrane, converting an extracellular signal (insulin binding) into intracellular signalling cascades.
What are the two main pathways activated by insulin signalling?
- Ras-Dependent Pathway (Growth Signals): Promotes cell growth and division.
- Ras-Independent Pathway (Glucose Regulation): Regulates glucose uptake and metabolism.
What happens in the Ras-dependent pathway?
IRS-1 is phosphorylated by the activated IR. Adaptor proteins (Grb2 and Sos) bind to phosphorylated IRS-1. Sos activates Ras (converts GDP-Ras to GTP-Ras). Activated Ras triggers the MAPK cascade: Ras → Raf → MEK → MAPK. MAPK enters the nucleus to alter gene expression, promoting cell growth and division.
What is the biological significance of the MAPK cascade in insulin signalling?
Amplifies the signal across the cytoplasm, regulates the expression of ~100 insulin-responsive genes, and stimulates cyclin and CDK production for cell division.
What happens in the Ras-independent pathway?
IRS-1 recruits and activates phosphoinositide 3-kinase (PI-3K). PI-3K converts PIP₂ (phosphatidylinositol 4,5-bisphosphate) into PIP₃ (phosphatidylinositol 3,4,5-trisphosphate). PIP₃ acts as a second messenger, recruiting PDK1 (PIP₃-dependent protein kinase) and PKB/Akt (Protein Kinase B).
What is the role of GLUT4 in glucose regulation?
GLUT4 is a glucose transporter stored in internal vesicles. Insulin signalling triggers GLUT4 movement to the plasma membrane, increasing glucose uptake in muscle and adipose tissue.
What are the outcomes of insulin’s Ras-independent pathway?
Increased glucose uptake into cells, conversion of glucose to glycogen (storage) and triacylglycerols (energy reserves), and amplification of the metabolic signal through lipid kinases and PKB.
What are insulin’s dual roles in the body?
- Growth Factor: Stimulates gene expression and cell proliferation through the Ras-dependent pathway.
- Glucose Regulator: Controls glucose uptake and metabolism via the Ras-independent pathway.
Why are insulin’s roles interconnected?
Growth and glucose metabolism are co-regulated to ensure energy is available during growth. Fibroblasts are an example of cells that use insulin as a growth factor.
What is diabetes mellitus, and what are its two types?
Type I Diabetes (IDDM): Caused by insulin deficiency, early onset; responds to insulin injections.
Type II Diabetes (NIDDM): Caused by insulin resistance (failure to respond to insulin), associated with obesity and late onset.
What causes insulin resistance in Type II diabetes?
Chronic high sugar levels desensitize insulin signalling. Insulin sensitivity can improve with exercise and strict dietary control.
How does PKB/Akt regulate glucose levels?
Stimulates GLUT4 insertion into the plasma membrane for glucose uptake and promotes glycogen synthesis in the liver and muscles.
How is the Ras-independent pathway terminated?
PTEN, a PIP₃-specific phosphatase, converts PIP₃ back to PIP₂. This prevents recruitment of PDK1 and PKB, shutting down signalling.
How can exercise and diet reverse Type II diabetes?
Vigorous exercise and calorie-restricted diets lower blood sugar levels. Reduced sugar levels restore insulin sensitivity in some cases.
What was the significance of the 2011 clinical trial on Type II diabetes?
Patients on a restricted 600 kcal/day diet for 2 months showed weight loss, restoration of insulin sensitivity, and reduced diabetic symptoms. Demonstrated that desensitization is reversible with lifestyle changes.
