Lecture 16 - Health and Disease in Signalling Flashcards
What mechanisms can there be loss of control of signalling?
Genetic - local/isolated, mutation of a common or rare component
Disease - local/isolated - local e.g. cholera, whole body e.g. diabetes
Where can loss of control occur?
At any point of the pathway
How can loss of control occur at the receptor level of GPCR?
Over-production of messenger/ligand
Under-production or inactive messenger
Failure of receptor to recognise ligand
Failure of receptor to activate G-protein
Failure of receptor to deactivate or always active
What are responsible for forming the core of the GPCR?
The transmembrane domains
What part of the GPCR interacts with the G-protein?
Cytoloops 2 and 3 and the C-terminal
What part of the GPCR interacts with the ligand?
N-terminal, exoloops and the core
Example how rhodopsin works?
It is a GPCR
It already has its agents attached
Light comes in and causes the G-protein to be activated
How is retinal to lysine?
Retinal is attached at TM7 to lysine
What do the surrounding amino acids of the lysine dictate?
The absorbance of the chromophore, they determine the colour of light this receptor can detect
Why are males mainly affected with colour blindness?
Because the genes for red and green are located on the X chromosome, around 2% of X chromosomes only have one ‘colour’ gene
What does a defect in G-alpha-12 cause?
Platelet dysfunction
What does a defect in G-alpha-t cause?
Night blindness
What does a defect in G-alphas cause?
McCune Albright syndrome
What does a defect in G-beta-3 cause?
Hypertension
What does a defect in G-alpha-i2 cause?
Adrenal cortical tumour
What causes a modification in G-alpha-s?
Cholera toxin
What causes a modification in G-alpha-i?
Pertussis toxin
G-protein and Cholera toxin:
Gram-negative rod-shaped bacteria
Produces cholera toxin
Colinises intestinal epithelial surface
Toxin is a hetero-oligoermic
Single catalytic subunit and a pentamer of B subunit
CTA1 subunit carries out NAD+ dependent ribosylaiton of G-s-alpha, which is just before the GTP binding site, resulting in activation of G-s-alpha
Activated G-s-alpha causes activation of adenylyl cyclase, Increase cAMP levels causes mis regulation ion channel and efflux of chloride ions
How can diseases be caused past the G-protein?
Failure of secondary messenger to be produced
Failure of secondary messenger to be removed
What does increased cAMP levels lead to increased? and how does this affect different tissues and organs?
Increased cAMP levels can lead to increased PKA activity
Adipose tissue, Epinephrine increase in triglyceride hydrolysis
Cardiac muscle, Epinephrine increase contraction rate
Kidney, Vasopressin reabsorption of water
Bone cells, Parathyroid hormone reabsorption of calcium from bone
Liver/Muscle, Increased glucose production
How is IP3 removed?
Degraded to IP2 or phosphorylated to IP4
How is cAMP removed?
Phosphodiesterases breakdown cAMP to AMP
How is cGMP removed?
Phosphodiesterases break down cGMP to GMP
What are the causes of type II diabetes?
Diet, Lack of exercise, Medical complication
What are adipocytes?
Fat cells
What does adipocytes secrete?
Wide range of hormones and cytokines
What is adipose tissue?
A dynamic endocrine organ
What are the functions of adipokines?
Lipid and lipoprotein metabolism Food intake and SNS activation Vasculature and angiogenesis Glucose metabolism/energy homeostasis Immune systen Extracellular matrix metabolism
