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Advanced Molecular > Receptor Signalling > Flashcards

Receptor Signalling Flashcards

1
Q

What are the three essential functions of ion channels?

A
  1. Transport ions across membranes
  2. Regulate membrane potentials
  3. Ca2+influx into the cytoplasm
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2
Q

What is a beta pleated sheet?

A

Beta strands connected laterally by at least two or three backbone hydrogen bonds forming a sheet

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3
Q

What is a subunit?

A

A single protein that forms with others to form protein complex

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4
Q

What are two structural features that are universal to all ion channels?

A
  • Transmembrane proteins made up of two or more alpha helices that cross the lipid bilayer
  • Made up of 2-6 subunits which usually surround the pore
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5
Q

What are ion channels classified into subgroups based on?

A
  • Gating mechanism
  • Ion selectivity of the pore defined by the physical size of the pore and the amino acids lining it
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6
Q

Which ion channel is the basis for all other ion channels?

A
  • pH-regulated K+ channel from bacterium
  • All other ion channels have derived through evolution of this channel, subunits and transmembrane domains change in numbers
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7
Q

Describe the structure of a simple ion potassium channel

A
  • 4 subunits each with two transmembrane domains which from around the pore
  • transmembrane domains more tightly packed on intracellular side
  • When ion binds it pushes open the gates and allows entry into the cell (highly specific)
  • K+ has to lose its water molecule to fit through
  • Membrane potential, mechanical stress and ligands cause the opening of gates
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8
Q

What are the two main functions of voltage gated ion channels?

A
  • Transport Na+ K+ to create action potentials in excitable cells
  • Transport Ca2+ into cell for 2nd messenger responses
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9
Q

Describe the structure of a voltage gated ion channel

A
  • Similar structure to K+ except additional helices S1-S4 to form a voltage sensing domain
  • Large polypeptides that extend into the cytoplasm (regulation)
  • Plugging mechanism- string of amino acids which when signalled can block the pore to stop ions entering
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10
Q

What are transient receptor potential channels? (TRPs) (+example)

A
  • Type of voltage gated ion channel but evolved to sense chemicals and physical stimuli
  • E.g. TRPV1 detects temperature over 40c and spicy foods hence why they elicit the same physical response
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11
Q

Describe ligand -gated ion channels (intracellular)

A
  • Similar to voltage-gated but controlled by ligand binding
  • Have 6 helices across the bilayer
  • No plugging mechanism
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12
Q

Give an example of an intracellular ligand-gated ion channel

A
  • Cyclin nucleotide-gated channels
  • N and C terminus are intracellular
  • C has a binding domain for cyclin nucleotide, when it binds the pore opens and Ca2+ enters
  • N terminus has a calmodulin binding domain which when bound due to enough Ca2+ it closes the ion channel
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13
Q

How are extracellular ligand-gated ion channels classified?

A

How many subunits they have, e.g. glutamate receptor has 4 subunits and nicotinic has 5

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14
Q

What makes the channels selective to the ions in extracellular LGIC?

A

The amino acids which line the pore

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15
Q

Describe a nicotinic receptor

A
  • Extracellular ligand gated ion channel
  • Nicotinic receptor is pentameric (5 subunits)
  • It has 4 transmembrane domains
  • Transmembrane 2 lines the pore which contains certain amino acids that make it negatively charged
  • Can also be called Cys-loop type receptor (nicotinic acetylcholine receptor)
  • Allow Na+, K+ and Ca2+ through due to the charge of the pore
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16
Q

Describe the Glutamate receptor family

A
  • Extracellular ligand-gated ion channel
  • Tetrameric (4 subunits)
  • 3 Transmembrane domains
  • Neurotransmitters bind to extracellular N terminus, C terminus is on the inside
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17
Q

What are the flip and flop isoforms of AMPA receptors which contribute to AMPA diversity?

A

Flip= Contains mRNA sequence which increases the length of C terminal and also makes the receptor Ca2+ permeable
Flop= mRNA sequence is spliced out making it not Ca2+ permeable- also faster desensitisation rates (quicker ligand dissociation)

AMPA receptors switch between the two for fine tuning effective synaptic transmission

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18
Q

Describe the P2X receptor family

A
  • Extracellular ligand gated ion channel
  • Trimeric
  • 2 transmembrane domains
  • Ligand is ATP (responds to 3 ATP molecules)
    -e.g. P2X7 receptor in macrophages deals with inflammation
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19
Q

What makes up the diversity of ligand receptors?

A

The combination of different subunits and the location
- Complexity provides good drug targeting

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20
Q

How are the nicotinic receptors targeted for nicotinic addiction?

A
  • nicotinic acetylcholine receptors exist as alpha helix 2-10- and beta 2-4 with a diff. affinity depending on composition and location
  • a4B2 are abundantly expressed in cortex and have high nicotine affinity
  • Smoking all the time leads to upregulated receptor
  • Polymorphisms in subunits a4 can lead to tobacco dependence but also good at quitting
  • If we can target these specific genes and subunits we can stop nicotine addiction
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21
Q

What causes autosomal dominant nocturnal frontal lobe epilepsy?

A
  • Mutation in nAChR in M2 region
  • 9 mutations now found
  • IN mutated genes there is a delay in response due to slow unblocking of closed receptors
  • When lots of activation happens all of this nicotinic transmitter is released at once causing seizures
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22
Q

How is a glutamate receptor like a clam shell?

A
  • Receptor goes from intracellular to extracellular
  • Glutamate binds to ligand binding domains and the domain is like a clam shell as the domain will close around the glutamate molecule
  • it is this closing action which pulls the other subunits apart and opens up the channel to create Na+ and K+ permeability
23
Q

What are the three types of Glutamate receptors and their amount of isoforms?

A
  • AMPA - (fast excitatory synaptic transmission) 4 isoforms
  • NMDA - (learning and memory) 5 isoforms
  • Kainate - (synaptic role but less than AMPA) 5 isoforms
24
Q

What happens to NMDA receptors during a stroke?

A

Excess stimulation leading to neuronal death

25
Q

What are G-protein coupled receptors?

A

Metabotropic receptors which are bound to a G-protein on the intracellular side of the membrane which mediate secondary responses

26
Q

Describe the structural features of GPCRs

A
  • 7 transmembrane domains (helices) which are linked by 3 extracellular loops and 3 intracellular loops
  • The N terminus is extracellular and is where the ligand binds
  • C terminus is intracellular where the G protein binds
27
Q

What happens when a ligand binds to the active site on a GPCR?

A
  • Opens up binding pocket between TM 5 and 6 and allows G protein to bind
  • Alpha subunit binds to binding site displacing GDP and replaces with GTP
  • This energy is used to become active and moves across the membrane to activate channels or enzymes etc directly
28
Q

How are GPCR classes distinguished?

A

By structural features of the extracellular domains i.e. the ligand binding sites

29
Q

What is meant by a tethered ligand?

A

Functional part of the protein which is initially connected but becomes free when modified

30
Q

How do protease-activated receptors in platelets work? (GPCRs)

A
  • N-terminus of PAR receptors contains sequence which acts as a tethered ligand
    Thrombin cleaves the receptor at this specific site in the N-terminus exposing the ligand
  • This exposed ligand binds to the extracellular
    loop of the receptor inducing conformational changes
  • This activates the receptor and triggers intracellular cascade, activates lots of other receptors
31
Q

How do different receptors work together in platelet formation?

A
  • Damaged endothelial exposes basal lumen which acts as a stimulus to integrin receptors
  • Collagen is bound to the site and anchors platelets to damaged site
  • Causes platelets to secrete ADP to activate other platelet receptors to activate integrin and fibrin which builds up platelets to heal the wound
32
Q

What are G proteins and what do they do?

A
  • Guanine nucleotide-binding proteins
  • Transmits signals from extracellular stimuli
  • Regulated by ability to bind and hydrolyse GTP to GDP
  • 3 subunits: alpha, beta, gamma
33
Q

How can GPCR be turned off?

A
  • Ligand unbinds
  • G protein can be switched off GTP is hydrolysed back to GDP, this can be helped by RGS proteins
  • Downstream proteins can switch off signalling message
34
Q

How are the Olfactory G proteins an example of how a response is produced?

A

-Odorant binds to receptor
- Olfactory g alpha subunit activated
- Displaced GDP for GTP
- a Moves through membrane and interacts with adenylate cyclase
- Adenylate cyclase uses ATP to produce cyclic amp
- Cyclic AMP acts as ligand to bind to Camp gated channels letting Na+ and Ca2+ in to send signals of what the smell is

35
Q

How many families of G proteins are there?

A

6

36
Q

Give examples of second messengers

A
  • Hydrophobis lipids
  • Small soluble molecules e.g. cAMP
  • Calcium ions
37
Q

Why do GPCR eleicit a bigger response

A

A single ligand binding to a single GPCR results in the phosphorylation of millions of proteins within the cell because multiple G proteins are activated due to one receptor and so on

38
Q

Explain what happens during cholera

A
  • Cholera toxin enters gut and binds to G protein (stimulatory GS alpha subunit)
  • Keeps it constantly activated
  • This activates adenaline cyclase, cyclic AMP and protein kinases
  • Increase in CL- secretion and Na+ secretion
  • Excess fluid in intestine leading to extreme dehydration and diarrhoea
39
Q

Explain how whooping cough works

A
  • Inhibitory alpha subunit binds
  • Inactivates the inhibitory G protein
  • Increase in cyclic AMP which leads to erosion of respiratory system causing coughing fits
40
Q

What causes Uveal Melanoma?

A
  • Mutation found in GQ alpha subunit
  • Occurs early on in tumour development
  • Causes blocking of GTP
  • Permanent signalling
  • Growth pathways always activated leading to tumour genesis
41
Q

What is the structure of cAMP and what does it do?

A
  • 10 isoforms
  • 12 TM domains but its 6 duplicated
  • Big catalytic domain on each of the duplicate subunits, when it is combined it becomes activated
  • Activated by Gas and inhibited by Gai
  • Activated by adenylate cyclase
42
Q

What are the steps in cAMP second messenger system?

A
  1. Ligand binds to receptor activating the G protein
  2. Alpha subunit exchanges GDP for GTP, allowing movement through the membrane and activation of adenylate cyclase
  3. Adenylate cyclase uses ATP to produce cAMP
  4. cAMP activates protein kinase A
  5. Protein kinase A phosphorylates lots of proteins in the cell to initiate a response
43
Q

How can signalling with G proteins be switched off?

A
  1. GTPase activity of Gas
  2. cAMP breakdown by phosphodiesterase
  3. Dephosphorylation of enzymes
44
Q

Give an example of a second messenger signalling cascade

A

B2 adrenoreceptor regulation of metabolism in liver and skeletal muscle

45
Q

What is cGMP second messenger system?

A
  • Enzyme is Guanylate cyclase which can be
    receptor bound or ‘free’
  • Converts guanosine triphosphate (GTP) to cGMP
46
Q

How are the signalling pathways controlled?

A
  • cAMP can be broken down by phosphodiesterase to help switch off pathway
  • cGMP can also be broken down by phosphodiesterase
  • Determined by rate of production, diffusion and removal of second messengers
47
Q

Explain the messaging involved in phospholipase CB

A
  • Hydrophobic lipids in the membrane are targeted by lipases to generate 2 types of second messengers
  • PIP2 is one of these hydrophobic lipids
  • GPCRs activate Phospholipase C breaks off head group to create Diacylglycerol and IP3 which are the two second messengers
  • DAG bound to membrane, IP3 moves through cytoplasm
  • Feedback mechanism = lipid kinases which add P groups back on to the lipids to turn off the activation of these molecules and reform PIP2
48
Q

Describe the structure of Phospholipase C (PLC)

A
  • X and Y subunits are present throughout all Phospholipase C isoforms and form the catalytic domain
  • Regulatory domains differ and determine which lipase in the membrane will bind to them
49
Q

Explain the activation of Protein Kinase C (PKC)

A
  • a target of PLC as it is DAG binding to PKC that causes dissociation of pesudosubstrate (fake) causing the binding site to open up
  • Phosphorylation of PLC can switch off activation (regulation)
50
Q

How are calcium membrane potentials regulated?

A
  • Ca2+ is a super important 2nd messenger
  • Calcium pump on plasma membrane to pump intracellular Ca2+ out if it gets too high
  • Also a pump on the ER membrane to pump Ca2+ out of cytoplasm into ER
  • Level of Ca2+ in ER is high as its a ‘store’
51
Q

How does the Ca2+ signalling pathway work?

A
  • PLC breaks down PIP2 into DAG and IP3 and the IP3 moves through cytoplasm and binds to IP3 receptors on ER membrane
  • Activate receptors to pump Ca2+ from ER into cell
  • Ca2+ is then restored in the ER
52
Q

How can Ca2+ be visualised in cells?

A

Fluorescent tags

53
Q

What are the two mechanisms involved in the de-sensitisation of GPCRs?

A

(Switching off receptor even if ligand is present)
- Receptor kinase (GRK) which binds to binding pocket of where G-protein would normally sit to stop downstream processes
- B arrestin which phosphorylates catalytic domain of receptor and stops G protein from binding
Causes receptor to be degraded

Advanced Molecular (13 decks)

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