Intracellular signalling Flashcards
What is signal transduction
Converting 1st messenger to cellular function
What are the stages of intracellular signalling
- reception
- signal transduction
- cellular response
What is the hierarchy in intracellular Signalling
- 1st messenger
- receptor
- G-protein
- effector enzyme
- 2nd messenger
- protein kinase
- target protein
- cell response
What is amplification
- 1st messenger —> large response
What is cross-talk in specificity
- 1st messenger stimulating diff. responses in diff cells
- 1st messenger bind to diff receptors on same cell
- 1st messenger stimulate different pathway
Example of specificity
- adrenaline
Why is there complexity in signal transduction
- 1000+ GPCRs
- 500+ protein kinases
- cross-talk
- cell-type specificity
What are G-proteins
- guanine nucleotide binding proteins
What is GTP
Guanosine trisphosphate
What is GDP
Guanosine diphosphate
What is the function of GTP
- high energy
- activate G-protein
What do G-proteins do as GTPases
What do ligand-receptors do
Hydrolyse GTP —> GDP
Energy released
Opposite to GTPases
What is the process of receptor associated G-proteins
- ligand binding —> GDP/GTP exchange
- effector activation —> 2nd messenger
- hydrolysis of GTP —> GDP
- re-association of G protein subunits
- loss of 2nd messenger
What is the effector enzyme and 2nd messenger of the following G-proteins:
- Gas
- Gai
- Gag
- adenylate cyclase (stimulation), cAMP
- adenylate cyclase (inhibition), cAMP
- phospholipase C (stimulation), DAG
What is the mechanism of cholera toxin (Gs)
- inhibits GTPase activity
- GTP remains “on”
- over-stimulation of adenylate cyclase
- accumulation of cAMP
- loss of Cl-
- osmotic gradient
- water loss
- dehydration
What are the syndrome of whooping cough
- paroxysmal cough
- whooping
What is the prevalence of whooping cough
- 40-50m cases/y
- >250000 death/y
What is the cause of whooping cough
- bordetella pertussis
- airborne respiratory droplet
- virulent factor: pertussis toxin
What is the treatment & prevention of whooping cough
- antibiotics
- vaccination
What is the mechanism of pertussis toxin (Gi)
- prevents GDP/GTP exchange by Gi
- “off” position
- accumulation of cAMP
- insulin secretion
- increased sensitivity to histamines
What is a 2nd messenger
- short-acting intracellular molecule
- rapidly formed/ released
- result of receptor activation
What are the 5 most common 2nd messengers
- cyclic AMP, cAMP
- cyclic GMP, cGMP
- diacylglycerol, DAG
- inositol 1,4,5-trisphosphate, IP3
- intracellular calcium, Ca2+
What is the production of cGMP catalysed by
- guanylate cyclase
- activated by NO
What enzyme breaks down cGMP
- PDE
- GMP formed
The activation of which G-protein causes the production of DAG, IP3 and Ca2+
Gq
Give examples of receptors activating Gq pathway
- angiotensin ii on AT1 receptor
- adrenaline on alpha 1-adrenegeric receptor
What is the mechanism for Gq activation
- ligand-binding —> GDP/GTP exchange
- effector enzyme activated —> 2nd messenger produced
- IP3 released in cytosol —> Ca2+ released
- DAG remains in memb. —> kinase C activated
What binds to ER to trigger Ca2+ release
- IP3
What are protein kinases
- enzymes facilitate transfer of P from ATP to specific aa (Ser, Thr, Tyr) in specific protein
What are the 3 main kinases groups
Serine/threonine
Tyrosine kinases
Dual-specificity (MAP –>MKKs)
How can kinases modulate protein function
- phosphorylation —> conformational change in protein
- phosphorylation of transcription factor
Check out slide 63 on lecture
Also check revision tip at bottom
What diseases are kinases inhibitors used to treat
- cancer
- cardiovascular disease
- HIV
- AD
What are G proteins
- heterotrimeric
- Gas, Gai, Gay
What are small GTPases
- monomeric
- Ras, Rho
Which two G-proteins have the opposite effect on cAMP
Gs, Gi
what is the production of cAMP catalysed by
Adenylate cyclase
what is the production of cGMP catalysed by
Guanylate cyclase
what do PDEs do
- break down cAMP, cGMP
- inhibit caffeine & viagra
