Receptors 2 Flashcards
(56 cards)
1
Q
What is signal transduction?
A
Signal transduction (also known as cell signaling) is the transmission of molecular signals from a cell’s exterior to its interior.
2
Q
Give 3 examples of extracellular signalling molecules
A
- hormones
- neurotransmitters
- growth factors
3
Q
For cells to respond to extracellular signalling molecules, what must they possess?
A
they must possess the appropriate “receptor”.
4
Q
Where are receptors founds and why?
A
Receptors can be intracellular.
But the majority of receptors are located at the cell-surface - because extracellular signalling molecules do not readily cross the plasma membrane
5
Q
Give two examples of hormones for which their receptors are intracellular
A
steroid and thyroid hormones
6
Q
What happens when the ligand binds to the receptor?
A
Ligand binding activates the receptor, which in turn directly or indirectly brings about a change in cellular activity
7
Q
How do receptors alter cellular activity?
A
- some receptors alter cellular activity directly
- many require “transduction” of the initial ligand binding event via other intracellular signalling components to generate a response, e.g. contraction, secretion, proliferation, differentiation, etc.
8
Q
What are the 3 “superfamilies” of cell-surface receptors?
A
- G protein-coupled (7TM) receptors
- Ligand-gated (receptor-operated) ion channels
- Receptors with intrinsic enzymatic activity
9
Q
Give an example fo a G protein-coupled (7TM) receptors
A
muscarinic acetylcholine receptors
10
Q
Give an example of a Ligand-gated (receptor-operated) ion channel
A
nicotinic acetylcholine receptors
11
Q
What are the two types of drugs that affects GPCRs?
A
- Agonists
2. Antagonists
12
Q
Give an example of a Receptor with intrinsic enzymatic activity
A
receptor tyrosine kinases (insulin receptor)
13
Q
What are the two types of drugs?
A
- Agonists
2. Antagonists
14
Q
What are agonists?
A
Drugs that bind to the receptor and activate it
- mimic the ligand
15
Q
What are antagonists?
A
Drugs that bind to the receptor, but do not activate it - block the effects of agonists
16
Q
Give two features of agonists
A
- Posses Affinity for receptor
* Posses Efficacy - ability of binding event to be converted to a signal transduction action
17
Q
Give two features of antagonists
A
• Have affinity but do not have efficacy
18
Q
Give two examples of agonists, stating the receptor they target.
A
anti-asthma
Target β2 adrenoceptor
I.e SALBUTAMOL, SALMETER
analgesia/anaesthesia
Target μ-opioid receptor
I.e MORPHINE, FENTANYL
19
Q
Give two examples of antagonists
A
cardiovascular
(e.g. hypertension)
Target β adrenoceptor
I.e. PROPRANOLOL, ATENOLOL
neuroleptics
(anti-schizophrenic)
Target D2 dopamine receptor
I.e. HALOPERIDOL, SULPIRIDE
20
Q
Why is it possible to make many drugs hat target the GPCR?
A
Different GPCR subtypes can respond to an amazing variety of stimuli
21
Q
What do sensory GPCRs detect?
A
Light (e.g. rhodopsin), odours and tastes
22
Q
What 4 things do different GPCRs respond to?
A
• Ions (H+, Ca2+) • Neurotransmitters (e.g. acetylcholine, glutamate) • Peptide and non-peptide hormones (e.g. glucagon, adrenaline) • Large glycoproteins (e.g. thyroid-stimulating hormone)
23
Q
What is the basic structure that all GPCRs share?
A
• Single polypeptide chain (300-1200 amino acids) • 7-transmembrane (7TM)- spanning regions • Extracellular N-terminal • Intracellular C-terminal
24
Q
Where are the two regions of GPCRs that can be responsible for ligand binding
A
• For some receptors the ligand binding site is formed by the transmembrane (TM) domains • In other cases the N-terminal region (and other extracellular domains) form the ligand binding site
25
Describe the steps that occur when a ligand binds to the GPCR upto the effector.
1. Ligand binds to the GPCR
2. GPCRs respond to ligand by changing their 3D shape- becoming active
3. Activated GPCR facilitates the activation of G proteins by interacting with the G protein
4. The GPCR-G proton interaction activates the G protein by causing the the GDP in the alpha subunit to be exchanged to GTP.
5. The α-βγ complex immediately
dissociates (into α-GTP + free βγ
subunits) and each can then interact
with effector proteins
6. The effector proteins can then generate second messengers to continue the signal
26
How is the G protein signalling terminated?
The α-GTP and/or βγ interaction with effectors lasts until the α subunit GTPase activity hydrolyses GTP back to GDP. α-GDP and βγ subunits then
reform an inactive heterotrimeric complex.
This stops effectors from being activated and second messenger system from occurring
27
What governs Receptor-G protein selection?
Activated GPCRs preferentially interact with specific types of G protein. The Gα subunit is a primary determinant.
In turn, Gα subunits and Gβγ subunits interact with specific effector proteins.
28
What are G proteins made up of?
G proteins are made up of 3 subunits (heterotrimetric)
1. Alpha subunit
2. Beta subunit
3. gamma subunit
The beta and gamma subunit function as a single unit as they are permanently together.
29
Which receptor does adrenaline target to stimulate adenylyl cyclase. Indicate the G protein used.
β-adrenoceptor
| G alpha s protein
30
Which receptor does adrenaline target to inhibit adenylyl cyclase. Indicate the G protein used.
Alpha2-adrenoceptor
| G alpha i protein
31
Which receptor does adrenaline target to stimulate phospholipase C
. Indicate the G protein used.
Alpha1-adrenoceptor
| G alpha q protein
32
Which receptor does acetylcholine target to inhibit adenylyl cyclase. Indicate the G protein used.
M2/M4 muscarinic receptor.
G alpha i protein
33
Which receptor does acetylcholine target to stimulate phospholipase C
. Indicate the G protein used.
M1/M3 muscarinic receptor.
G alpha q protein
34
Give two examples of toxins that interfere with the G protein function
cholera toxin (CTx) and pertussis toxin (PTx)
35
How does the cholera toxin work?
* Cholera toxin binds to the cell and injects an enzyme which causes covalent modification for alpha s subunit and prevents it from from being switched off - lost its GTPase activity .
* In presence of cholera toxin we get sustained alpha s mediated signalling
36
How does the cholera toxin cause diarrhoea
In presence of cholera toxin we get sustained alpha s mediated signalling and in the intestinal lining, it causes alpha s to activate adenelyl cyclase which produces a second messenger cyclic AMP which open water channels and releases water and electrolytes out of cells and into lining of the gut. Results in dehydration, diarrhoea.
37
How does the pertussis toxin work/
Pertussis toxins are produced in the airways/ respiratory tissues and binds to the cells and inject an enzyme which covalently modifies alpha i subunits in the cells. Stops alpha i subunits from releasing GDP.
Toxin prevents GDP to GTP exchange - cannot pass on signal even when receptor stimulated
38
Give 4 examples of effectors that are enzymes
1. ADENYLYL CYCLASE
2. PHOSPHOLIPASE C
3. PHOSPHOINOSITIDE 3-KINASE (PI3K)
4. cGMP PHOSPHODIESTERASE
39
What does ADENYLYL CYCLASE do?
ATP ————> cyclic AMP
40
What does PHOSPHOLIPASE C do ?
PIP2———————-> IP3 + DAG
41
What does PHOSPHOINOSITIDE 3-KINASE (PI3K) do?
PIP2 —————-> PIP3
42
What does cGMP PHOSPHODIESTERASE do?
cyclic GMP —————-> 5’-GMP
43
Give two examples of effectors that are ion channels
1. VOLTAGE-OPERATED Ca2+ CHANNELS (VOCCs)
2. G PROTEIN-REGULATED INWARDLY-RECTIFYING
K+ CHANNELS (GIRKs)
44
Describe the steps taken for an agonist to lead to the phosphorylation of target proteins
1. Agonist binds to GPCR and activates it
2. Activated GPCR interacts with G protein
3. GPCR-G interaction activates G protein by causing GDP on alpha s subunit to be exchanged to GTP
4. The G protein dissociates into alpha s subunit and beta gamma subunit
5. The alpha s GTP will interact with the adenylyl cyclase
6. This causes AC to increase its activity(stimulation) and convert ATP into cyclic AMP - the second messenger
7. When the cAMP concentration rises in the cell, two cAMP molecules interacts with the regulatory subunits of the PKA.
8. This allows the regulatory subunits to release the catalytic subunit which acts as the protein kinase and phophorylates target proteins in the cell
45
Give 3 examples of Gs-coupled receptors and state the agonist.
1. β-adrenoceptors
- adrenaline
2. D1-dopamine receptors
- dopamine
3. H2-histamine receptors
- histamine
46
How does an agonist lead to the inhibition of adenylyl cyclase and what is the result of this?
1. Agonist binds to GPCR and activates it.
2. Activated GPCR interacts with G protein
3. GPCR-G interaction activates G protein by causing GDP on alpha i subunit to be exchanged to GTP
4. The G protein dissociates into alpha i subunit and beta gamma subunit
5. The alpha i GTP will interact with the adenylyl cyclase
6. This causes AC to decrease its activity(inhibition)
7. Therefore, cyclic AMP is not made from ATP
8. So cyclic AMP does not activate signalling pathways, PKA
47
Describe the agonist stimulated regulation of phospholipase C
1. Agonist binds to GPCR and activates it.
2. Activated GPCR interacts with Gq protein
3. GPCR-G interaction activates G protein by causing GDP on alpha q subunit to be exchanged to GTP
4. The G protein dissociates into alpha q subunit and beta gamma subunit
5. The alpha q GTP will interact with the enzyme phospholipase C (PLC)
6. The PLC becomes activated and hydrolyses PIP2 into IP3 and DAG
7. The IP3 diffuses through the cytoplasm and reaches IP3 receptors on the endoplasmic reticulum, causing them to open and release calcium ions into the cytoplasm from the endoplasmic reticulum store. IP3 is a calcium mobilising second messenger signal
8. DAG its own protein kinase, protein kinase C (PKC) which is activated and thus goes on to phosphorylate its own cellular substrates
48
Give 3 examples of Gq -coupled receptors and their agonists
α1-adrenoceptors - adrenaline
M1-muscarinic receptors - acetylcholine
H1-histamine receptors -
49
Give an example of signal amplification
For example, a few molecules of adrenaline binding to cell surface β-adrenoceptors may cause a relatively massive cellular response
The β-adrenoceptor ———> Gs protein ———> adenylyl cyclase part of the cascade causes relatively little amplification. Nevertheless, activation of adenylyl cyclase generates many molecules of cyclic AMP each of which then activate many of the enzyme PKA.
50
Describe the signalling pathway for inotropy in the heart
1. Adrenaline or noradrenaline binds to a β1-adrenoceptor
2. The β1-adrenoceptor interacts with Gs proteins
3. GPCR-G interaction activates Gs protein by causing GDP on alpha s subunit to be exchanged to GTP
4. The G protein dissociates into alpha s subunit and beta gamma subunit
5. The activated alpha s subunit interact with adenylyl cyclase which converts ATP to cAMP.
6. The cAMP activates PKA
7. The PKA phosphorylates voltage operated calcium channels present in the membrane of the ventricular myocyte
8. The VOCC is normally opening and closing due to the signals from the SAN to depolarise the membrane.
9. Phosphorylation by PKA changes the kinetics of the channels so that the next time it opens, it allows more calcium into the myocyte. Changes how much calcium enters each time there is a depolarisation
10. More Calcium entering triggers calcium induced calcium release inside the cell.
11. The trigger calcium binds to the calcium induced calcium release channels on the sarcoplasmic reticulum .
12. This causes the channels to open causing further influx of calcium
13. Thus the heart cell contracts more forcefully
51
Describe the regulation of chronograph of the heart
Intrinsic rate of the heart is regulated by the
sinoatrial node (SAN) which has
parasympathetic innervation which releases ACh
. The M2 receptors have the Ai subunit and so as
well as adenylyl cyclase inhibition. More K+
channels are open which slows down the firing
rate having a reduced chronotropic effect.
52
Describe the signalling pathway for smooth muscle contraction to cause vasoconstriction of arterioles
1. Noradrenaline binds to α1-adrenoceptors and activates it.
2. Activated α1-adrenoceptors interacts with Gq protein
3. GPCR-G interaction activates G protein by causing GDP on alpha q subunit to be exchanged to GTP
4. The G protein dissociates into alpha q subunit and beta gamma subunit
5. The alpha q GTP will interact with the enzyme phospholipase C (PLC)
6. The PLC becomes activated and hydrolyses PIP2 into IP3 and DAG
7. The IP3 diffuses through the cytoplasm and reaches IP3 receptors on the sarcoplasmic reticulum, causing them to open and release calcium ions into the cytoplasm from the sarcoplasmic reticulum store.
8. DAG has its own protein kinase, protein kinase C (PKC) which is activated and thus goes on to phosphorylate its own cellular substrates
9. Combined effect of increased calcium release and increased PKC activity causes a sustained contraction of smooth muscle that causes a sustained effect on blood pressure
53
What causes bronchoconstriction?
Parasympathetically released acetylcholine can interact with bronchiolar smooth muscle M3 -muscarinic receptors to cause bronchoconstriction.
54
Describe the signalling pathway for Modulation of neurotransmitter release
1. Morphine binds to u-opioid receptor (GPCR) and activates it.
2. Activated GPCR interacts with G protein
3. GPCR-G interaction activates G protein by causing GDP on alpha i subunit to be exchanged to GTP
4. The G protein dissociates into alpha i subunit and beta gamma subunit
5. The beta gamma subunit binds to VOCC and inhibits it.
6. Thus , when the next depolarisation occurs, fewer calcium ions enter and so fewer neurotransmitters are released.
55
What are the advantages of GPCR SIGNAL TRANSDUCTION IN BIOLOGICAL MEMBRANES ?
1. DIVERSITY: Diverse range of stimuli, receptors, G proteins
and effectors.
2. SPECIFICITY: Specific ligand-receptor interactions, specific
G protein α-subunits (βγ) recruited, which are coupled to particular effector pathways.
3. AMPLIFICATION: “Gain” control on all signalling pathways,
allowing relatively small changes in extracellular signals to elicit significant changes in cellular behaviour.
56
Give 4 examples of Gi-coupled receptors and their agonists
1. a2-adrenoceptor
2. D2-dopamine receptor
3. u-opioid receptors
4. M2/M4 muscarinic acetycholine receptors
