L16: When signalling goes wrong Flashcards
How can signalling control be lost?
- Genetic: localised/ isolated through to wide spread e.g. mutation of commmon/ rare component
- Disease: local (e.g. cholera and whooping cough) /isolated (diabetes) or whole body
Where can signalling control be lost?
At any place in the pathway- primary message receptor, transducer, effector signal (secondary message), signal removal
How does G-protein, GPCR and associated protein levels vary in cells?
Not all are expressed in all cells
- expression levels may change during development/ growth
- changes in specific receptors may have localised effects
How can GCPR disease be caused at receptor level?
- overproduction of messenger/ ligand e.g. hyperparathyroidism
- underproduction/ inactive messenger e.g. nephrogenic diabetes insipidus (lack of AVP)
- failure of receptor to recognise ligand e.g. ND1
- failure of receptor to activate G protein e.g. ND1
- failure of receptor to deactivate e.g. hyperthroidism
How do TM domains in GCPR form the core?
- N terminal, exoloops and core interacts with ligands
- Cytoloops 2&3 and the C terminal interact w G protiens
possible interactions w all3 subunits of G protein
What are the genetics of colour blindness?
X chromosome linked and recombination can result in altered gene levels
List how different G proteins are related top diseases
- G alpha 12 defects result in platelet dysfunction (clotting failure)
- G alpha t (transducin) → night blindness
- G alpha s → McCune-Albright syndrome
- G beta 3 → hypertension
- G alpha i2 → adrenal cortical tumour
These are genetic but we can also get modifications e.g. G alpha s → cholera toxin & G alpha i→ pertussis toxin (whooping cough)
Explain the pathology of cholera
- caused by gram -ve rod shaped bacteria, producing the cholera toxin which colonises intestinal epithelial surface
- toxin is a heterogliomeric that causes massive fluid
- toxin formed of single catalytic A subunit and a pentamer of B subunits
- A subunit is taken into cell and cleaved
How is G s alpha activated?
CTAI subunit NAD+ dependent ADP ribosylates G s alpha prior to GTP binding
What can increased cAMP levels cause?
Misregulation of ion channels and efflux of chlolride ions
How can post G-protein diseases occur?
Failure of secondary messenger to be produced
- may result from failure of G protein to recognise the effector or from effector to produce secondary message
Failure of secondary messenger to be removed from cell
- over production of messenger
- failure of activation of removal system
- lack of activity in removal system
Increased cAMP can lead to increased PKA activity. What effects can this have?
- adipose tissue: epinephrine increase in triglyceride hydrolysis
- cardiac muscle: epinephrine increases contraction rate
- kidney: vasopressin reabsorption of water
- bone cells: parathyroid hormone reabsorption of Ca from bone
- liver/ muscle: increased glucose production
How are signals terminated?
By removing secondary messengers
- PLC IP3 degraded to IP2 or phosphorylated to IP4
- cAMP phosphodiesterases (PDEs) breakdown cAMP to AMP
- cGMP PDEs breakdown cGMP to GMP
What causes type 2 diabetes?
Failure of the body to correctly manage blood glucose
- pathway causing fault is unknown
Adipocytes are the only endocrine organ to dramatically increase in size during a person’s lifetime. True or false?
True, they have been shown to secrete a wide range of cytokines and hormones also
