pharmacology Flashcards
(83 cards)
What does intracellular binding describe?
Hint - which set of stairs is involved in every single secondary messenger system?
ligand + receptor binding → enzyme cascade activation → cellular response/s
What do receptors allow?
Hint - signals + intracellular or extracellular change
- extracellular signals across PM to respond to stimuli
- so extracellular substances (can’t pass through) → intracellular change
Which molecular responses can receptors allow?
Hint - 2 are very cellular, one to do with channels and one to do with +VE feedback
- opening of ion channels
- secretion of other signalling molecules
- cell motility (movement)
- modification of cell cycle
What type of signalling is utilised by type 2 and type 3 receptors?
- type 2 receptors → G-protein pathway
- type 3 receptors → enzyme-linked cell surface pathway
Describe type 1 receptors.
Hint - type of transmission, what its coupled to how many times its repeated
- associated w/ fast neurotransmission (GABA, 5-HT, ACh)
- receptors are coupled to ion channels and sit on the cell membrane like subunit
- subunits repeated 4/5x within membrane
What is a ‘binding domain?’
where small molecule (substrates) will bind
Describe the example of type 1 nicotinic ACh receptors (stimulatory) and how they work.
- consists of 5 membrane spanning subunits: • 2 x α (binding domain for ACh) • β • γ • δ 1. 2x ACh molecules bind to 2 alpha units 2. opens ligand-gated Na+ ion 3. depolarises cell as influx of Na+
Describe type 2 receptors and how they work.
Hint - 4/5 → ligand binds domain, signal transmitted, domain + signalling molecule and GP activation
- single polypeptide chain (400-500 AA residues)
- ligand attaches to binding domain → signal travels through chain → signalling molecule (receptor) binds to domain → G-protein activated
Draw, label and describe the structure of a type 2 receptor.
Hint - looks like the piping of plumbing in the house
- receptor protein forms seven transmembrane α-helices embedded in membrane
- long intracellular (3rd) loop between α-domains 5 and 6 where G protein couples to receptor
(see notes for diagram)
Describe G-proteins and their subunits.
(Hint - activity, all 3 types of radiation in physics, describe the most active and then how the other two connect to the membrane when inactive what all 3 subunits form)
- highly-mobile intracellular membrane proteins with 3 subunits (α, β and γ)
- α subunit:
• more mobile than β and γ subunits
• functions as a GTPase enzyme (converts GTP → GDP) - β and γ subunits – form complex which is v. hydrophobic therefore they stay closely associated w/ the membrane
- when inactivated, all 3 subunits form complex with GDP bound to α-subunit
(see notes for diagram of resting state)
Describe the 3 stages of (G-protein-coupled) activation of type 2 receptors.
(Hint - use the diagrams on your notes)
1)
- ligand + receptor (bind) → conformational change in α, β and γ complex
- α-subunit dissociates from other 2, converts: GDP → GTP
2) α-subunit coupled to GTP, associated with specific allosteric target enzyme (e.g. adenylate cyclase)
3)
- α subunit hydrolyses GTP → GDP
- inactivates enzymatic ability of α-subunit + allows activation of target enzyme
- inactive α-subunit re-associates with β and γ complex
- G-protein changes: substrate → product.
(see notes for diagrams)
What can a G-protein mechanism act as and how?
- signal amplifier
- single activated receptor can activate several G-proteins
Which 4 membrane proteins do targets for G proteins activate?
(Hint - Na+)
1) adenylate cyclase – producing intracellular cAMP
2) guanylate cyclase – producing intracellular cGMP
3) phospholipase C/inositol phosphate system
4) regulators of ion channels
What is cAMP produced from a type 2 (G-protein) receptor, how is it inactivated, what does it specifically target and what are these molecules subsequently used for?
(Hint - 2, PK and DEs)
• cAMP (cyclic 3’,5’-adenosine monophosphate) acts as a secondary messenger → inactivated by hydrolysis into 5’-AMP
• cAMP:
- specifically targets inactive protein kinases → activate (ATP as phosphate source)
- activate PKs to phosphorylate (activate) downstream enzymes
Give an example of a role that cAMP has in cells.
the breakdown of glycogen in β-adrenoceptors
Which involvements does cAMP have in cells other than β-adrenoceptors, how it can be broken down and how can it be inhibited?
(Hint - cardiac, muscle, p, drugs)
- increased activity of voltage-gated Ca2+ channels in the heart
- inactivation of myosin light chain kinase in SM
- cAMP broken down by phosphodiesterase
- inhibited by drugs (i.e. caffeine)
Describe the 5 stages by which receptor guanylate cyclases act as an example of type 2 receptor. Which secondary messenger is involved?
(Hint - EC + ligand, IC domain + GP, gc → cG, cG binds cG-PK, GK + pi → Thr/Ser residues)
1) ligand binds on extracellular domain
2) G-protein activates intracellular domain (guanylyl cyclase)
3) guanylyl cyclase produces: → cGMP
4) cGMP binds to cGMP-dependent protein kinase (G-kinase)
5) G-kinase phosphorylates downstream proteins on threonine/serine residues
- cGMP = secondary messenger
(see notes for diagram)
How does the receptor phospholipase C (or inositol phosphate system) act as an example of a type 2 receptors and which actions are steps associated with?
(Hint - PIP →
- GP and p-lipase
- PIP splits → Dog + Inspo
- both these products act as 2s
- Dog → PKC → targets
- Inspo leading to Ca release)
- based on phospholipid phosphoinositide-4,5-diphosphate (PIP2)
1. G-protein activates target enzyme (phospholipase)
2. phospholipase splits: PIP2 → diacylglycerol (DAG) + inositol-1,4,5-triphosphate (InsP3)
3. InsP3 + DAG act as 2° messengers
4. DAG activates PKC which is serine/threonine kinase, → phosphorylates certain target enzymes
5. InsP3 binds to endoplasmic receptors → open endoplasmic Ca2+ channels → influx of Ca2+ into cytosol needed for certain actions
How do regulators of ion channels act as an example of type 2 receptors? Give a specific example of this in the body.
(Hint - all about GPs and muscu receptors, main NT, K)
- G-proteins directly activate ion channels.
- e.g. interaction of ACh and muscarinic receptors opens K+ channels via G-protein pathway
What is a kinase?
enzyme that catalyses the transfer of phosphate groups
What are the 4 forms of type 3 receptor?
Hint - TYR, LINKED TYR, TYR P, SER/THR
a. Receptor tyrosine kinases - TYR
b. Receptor linked tyrosine kinases – LINKED TYR
c. Receptor tyrosine phosphatases – TYR P
d. Receptor serine/threonine kinases – SER/THREIONINE
State the six stages by which tyrosine kinases work as an example of type 3 receptors and give 2 examples of molecules.
(Hint - ligand EC, change + 2 poly → dimer, tyr K + Pi, auto Pi by tails, SH2 + SH3, genes affected and cells respond
- 2 hormone examples)
1) ligand binds to extracellular binding site
2) conformational change in shape → 2 polypeptides form dimer
3) cytoplasmic tyrosine kinase activated by phosphorylation
4) autophosphorylation → cytoplasmic tail groups can phosphorylate each other (+Pi)
5) activated tyrosine kinases (phosphotyrosines) now binding sites for proteins with SH2 + SH3 domains → act as ligands.
6) proteins/enzymes + transcription factors are activated → gene transcription altered → cellular response
- i.e. receptors for growth factors + insulin
(adapter protein – an important class of protein)
(see notes for image of process)
State the molecule that each abbreviation stands for and state the other names where applicable:
a) GAP (Hint - GTPase…)
b) GEFs (Hint - a type of DNA base exchanger + how to ask for help in WW1)
c) Raf (Hint - ser/thr and k.)
d) ERK (Hint - an EC type of SR kinase)
e) TF
f) FAK (Hint - like adjusting + then sticking on your glasses)
a) GTPase activating protein
b) Guanosine exchange factors i.e. Sos
c) serine/threonine kinase i.e. MAPKKK
d) extracellular signal regulating kinase
e) Transcription factor
f) Focal adhesion kinase
Explain integrins and the integrin protein family as an example of receptor-linked tyrosine kinases type 3 receptors.
(Hint - all about cell parts attaching, 2 types of radiation and di elements)
- integrins → typical example
- proteins which function by attaching cell cytoskeleton + ECM → biochemically sensing whether adhesion occurs
- α + β subtypes which form transmembrane heterodimers (2 different proteins joined)
