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GPCRs Flashcards

1
Q

Describe the general structure of a GPCR.

A

Integral membrane protein with 7 TM domains

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2
Q

How many GPCRs are encoded by the human genome?

A

~800

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3
Q

Why are GPCRs hard to crystallise? And how is this overcome?

A

They are membrane and have flexible regions. Overcome by using lipid cubic phase crystallography and detergent micelles.

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4
Q

What types of signals activate GPCRs?

A

Photons, exogenous small molecules, neurotransmitters, hormones, peptide hormones and chemokines

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5
Q

Give an example of a GPCR that responds to photons?

A

Rhodopsin

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6
Q

When are exogenous small molecules used to activate GPCRs?

A

During smell/taste responses

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7
Q

What is the β-adrenergic receptor used as a drug target for?

A

Target for β-blockers during the treatment of angina.

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8
Q

Describe the activation process involved in GPCR activation.

A

Extracellular ligand binds to the GPCR and causes a conformational change (shift in helices) to create a G protein binding site. Upon binding, a conformational change in Gα allows exchange of GDP (bound to G protein) for GTP. Activated G protein subunits cause downstream signalling - mediate effector protein activation.

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9
Q

How do GPCRs allow for signal amplification?

A

The receptor remains active, with a G protein binding site, for as long as the signal molecule is bound to the receptor. This means that multiple G proteins can bind and become activated by the same receptor.

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10
Q

Which G protein subunit usually mediates action?

A

Gα

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11
Q

What is catalysed by adenylyl cyclase?

A

The formation of cAMP from ATP - cyclisation reaction, releases PPi.

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12
Q

Describe the structure of adenylyl cyclase.

A

Membrane bound with a largely cytosolic catalytic domain.

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13
Q

Which responses tend to be mediated by cAMP signalling as a second messenger?

A

Hormone induced responses

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14
Q

Why is cAMP short-lived in the cell?

A

It is hydrolysed by phosphodiesterase to give 5’AMP - which cannot as a second messenger.

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15
Q

How does cAMP binding activate PKA?

A

PKA is a heterodimer - when cAMP binds to the regulatory subunit, the catalytic subunit is released and can diffuse to the effector proteins.

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16
Q

Give an example of a fast response mediated by cAMP signalling.

A

There is a fast response to serotonin - cAMP levels rise, activate PKA which phosphorylates and inhibits a K+ channel.

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17
Q

Give an example of a slow response mediated by cAMP signalling.

A

Somatostatin-induced cAMP signalling - cAMP levels rise, actviate PKA, catalytic subunits go into the nucleus and activate CREB - TF which stimulates transcription of a target gene.

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18
Q

How is PLC-β associated with the membrane?

A

Via non-catalytic alpha helices.

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19
Q

Give examples of responses where GPCRs activate PLC-β.

A

Ach signal to cause amylase secretion in the pancreas. Thrombin signal to cause platelet aggregation.

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20
Q

What is catalysed by PLC-β?

A

Hydrolysis of the ester in phosphatidylinositol-4,5-bisphosphate to produce DAG and IP3

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21
Q

How does IP3 act as a second messenger?

A

Travels to the ER - opens IP3-gated calcium ion channels to release calcium ion stores from the ER

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22
Q

How are waves of calcium release generated?

A

Calcium released can activate other nearby IP3 receptors (ryanodine) but inhibits the receptors at high calcium concentrations - positive and negative feedback

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23
Q

Describe the effect of calcium waves in a fertilised egg cell.

A

Sperm delivers PLC-β to the egg during fertilisation - results in calcium release. Oscillating waves of calcium release makes the egg cell unresponsive to another sperm.

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24
Q

Describe the effect of calcium waves in liver cells.

A

Vasopressin binds a GPCR which activates PLC-β to stimulate glycogen breakdown. If there is more vasopressin present, there are more spikes in the calcium concentration - strength of signal coupled to calcium oscillation.

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25
How are changes in calcium concentration detected in a cell?
By calcium binding to Calmodulin
26
Describe the structure of Calmodulin.
Has 4 calcium ion binding sites within an E/F hand motif (helix-loop-helix). Calcium ions are coordinated by negative regions in the helix. When calcium is bound, the two ends of calmodulin become rigid and the middle helix can form correctly - activating calmodulin.
27
Describe the structure and activation of CAMKs (Ca/calmodulin dependent kinases).
Large enzymes with 6 calmodulin binding sites. Calcium binding allows calmodulin to bind the linker region between CAMK subunits - releases catalytic domains. CAMK autophosphorylates when calmodulin is bound to increase enzyme activity.
28
How is CAMK deactivated?
By dephosphorylation by a phosphatase.
29
How does a high frequency of calcium release improve enzyme activity?
Autophosphorylation occurs between calcium waves and when these are at a high frequency the enzyme is not dephosphorylated before the next calcium wave - enzyme activity increases until calmodulin has bound each binding site and all 6 catalytic domains have been released.
30
Summarise the downstream signalling that occurs following GPCR activation of PLC-β.
PLC-β produces IP3 and DAG. DAG remains in the membrane and activates PKC. IP3 moves to the ER membrane and opens calcium channels. Calcium released acts as a second messenger. Calcuim binds calmodulin which activates CAMKs. The ultimate effectors of the signalling pathway are downstream of CAMKs.
31
How can GPCRs change the electrical activity of cells?
By gating ion channels involved in action potential generation.
32
How does acetylcholine reduce heart rate by changing the electrical potential in pacemaker cells?
Ach binds nicotinic GPCR - activates Gi protein. Inhibitory Giα subunit inhibits adenylyl cyclase - results in decreased levels of cAMP. Without the cAMP spike, membrane potential is more negative and harder to depolarise - resulting in a reduced firing rate.
33
How many olfactory receptors are encoded in the human genome?
~350
34
Why do some animals have more olfactory receptors than humans?
They rely on their sense of smell more - humans don't need as many olfactory receptors and the human genome contains pseudogenes that originated from mouse olfactory receptors.
35
Describe the downstream signalling following detection of a smell.
Odorant binds GPCR - activates Golf protein. Golf activates adenylyl cyclase - increase in cAMP level opens cAMP-gated sodium channels. This decreases the membrane potential and makes the membrane easier to depolarise - action potential triggered.
36
How does the structure of the retina support the argument that there is no intelligent design in nature?
Light is detected at the back of the retina (back-to-front layout)
37
Where are photoreceptor cells found?
At the back of the retina, connected to a pigmented epithelium.
38
Why must photoreceptor cells be connected to an epithelium?
Photoreceptor cells are highly metabolic cells, producing high amounts of ROS - need to be protected and fed by epithelial cells.
39
What are the main difference between rod and cone photoreceptor cells?
Rods - B+W vision, but are more sensitive to light, working in both bright and dim conditions Cones - allow colour vision in bright light, have pigments for red, blue and green light
40
What are bipolar cells?
Cells that synapse with photoreceptor cells at one end and ganglion cells at the other end.
41
What do the axons of ganglion cells do?
Make up the optic nerve
42
Describe the structure of a rod cell.
Made up of a cell body, inner segment and an outer segment. The outer segment consists of membrane stacks - forming disks which each hold ~150,000 rhodopsin molecules.
43
What is rhodopsin?
A GPCR that contains retinal (chromophore) for detecting light. When activated by light, rhodopsin binds the G protein, transducin.
44
How is retinal attached to rhodopsin?
Connected to a lys residue via a schiff base
45
How does light activate the rhodopsin?
Causes photoisomerisation of 11-cis retinal to all-trans retinal (specifically by rotation of the C11=C12 bond)
46
How does photoisomerisation of retinal activate rhodopsin?
Causes a shift in the helices of rhodopsin, which creates the transducin binding site.
47
Describe the resting state of photoreceptor cells.
Rhodopsin is inactive (11-cis retinal). Cation channels are open. Cell is depolarised - results in glutamate release. Glutamate inhibits ON bipolar cells - no action potential triggered.
48
Describe the active state of photoreceptor cells.
Light causes photoisomerisation of retinal. Shift in rhodopsin helices leads to transducin binding. Cation channels closed. Cell is hyperpolarised - no glutamate released. No inhibition of ON bipolar cell - action potential is triggered.
49
What is the difference between an ON and an OFF bipolar cell?
OFF bipolar cells have different glutamate receptors which fire an action potential upon glutamate release.
50
How are the cation channels in photoreceptors gated?
Gated by cGMP. When transducin is activated it activates cGMP phosphodiesterase - hydrolysis of cGMP opens channels and causes hyperpolarisation in the presence of light.
51
Name the proteins involved in returning the activated photoreceptor to the resting state.
GTPase activating protein (GAP), guanlyl cyclase, rhodopsin kinase, arrestin
52
How does GTPase activating protein contribute to the return to the resting state in a photoreceptor cell?
Inactivates transducin
53
How does guanylyl cyclase contribute to the return to the resting state in a photoreceptor cell?
Stimulated by low concentrations of calcium ions to produce more cGMP - opens cation channels.
54
How does rhodopsin kinase contribute to the return to the resting state in a photoreceptor cell?
Stimulated by low concentrations of calcium ions to phosphorylate the tail of rhodopsin - makes it unable to activate transducin.
55
How does arrestin contribute to the return to the resting state in a photoreceptor cell?
Binds the phosphorylated tail of rhodopsin (once phosphorylated by rhodopsin kinase) and prevents transducin binding.
56
What is the purpose of the retinoid cycle?
To remove the all trans-retinal by hydrolysing the schiff base and to replace it with 11-cis retinal by forming a new schiff base.
57
What does the GRK1 kinase do?
Phosphorylates rhodopsin to give the meta II-Gt state to allow arrestin binding. GRK1 only phosphorylates activated rhodopsin - is itself activated by the active GPCR.
58
What is the purpose of arrestin?
To prevent transducin binding to rhodopsin whilst the photoreceptor cell is returning to the resting state. Arrestin binding stimulates clathrin-mediated endocytosis of some other GPCRs.
59
Give a summary of the rhodopsin cycle.
1. Rhodopsin is hit by light –isomerises retinal 2. Leads to the binding of transducin – signal is propagated to the bipolar cell 3. GRK1 kinase phosphorylates the rhodopsin to give the Meta II-GRK1 state 4. Arrestin binds phosphorylated rhodopsin and removes all-trans retinal to give opsin 5. 11-cis-retinal binds to opsin to regenerate rhodopsin
60
When is nitric oxide used as a signalling molecule?
In the vascular system - communication between epithelial cells and smooth muscle cells.
61
How does acetylcholine stimulate relaxation of smooth muscle cells?
1. Ach binds GPCR on membrane of epithelial cells 2. Activated G protein activates PLC-β to produce IP3 3. IP3 goes to the ER where it opens calcium channels - releasing calcium stores from the ER. 4. Increased calcium ion concentration activates NO synthase 5. NO synthase produces nitric oxide from arginine 6. NO is a diffusible gas messenger - diffuses from epithelial cells to smooth muscle cells. 7. NO activates guanylyl cyclase in smooth muscle cells - increase in [cGMP] causes rapid relaxation of smooth muscle in blood vessels, increasing blood flow.
62
How does viagra work?
In erectile dysfunction, little NO is produced - meaning cGMP is hydrolysed at the same rate it is produced and smooth muscle cannot relax. Viagra inhibits cGMP phosphodiesterase - less cGMP hydrolysis, meaning that smooth muscle relaxes and there is increased blood flow -> erection

ICB - Cell Signalling (5 decks)

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