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ICPP > Drug Targets - The Receptors > Flashcards

Drug Targets - The Receptors Flashcards

1
Q

What are the different types of intracellular signalling?

A
  1. Signalling by secreted molecules
  2. Signalling by plasma membrane bound molecules.

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2
Q

Signalling by secreted molecules - Paracrine?

A
  • The signalling molecule is secreted by the signalling cell into the interstitial space within a tissue.
  • The signalling molecule is recognised by the target cells and produces a consecrated response within the tissue
  • The signalling molecule is known as a local mediator as it is acting within the interstitial space to signal to adjacent cells.
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3
Q

Signalling by secreted molecules - Endocrine.

A
  • The signalling molecule is released from the signalling cell into the bloodstream where it circulates around the body to target cells.
  • Finding target cells in distant tissues.
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4
Q

Signalling by secreted molecules - Synaptic.

A
  • Arrival of an action potential to the presynaptic membrane releases a transmitter into the synapse.
  • This transmitter is recognised by receptors on the target cells to produces a electrical response in the target cell.

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5
Q

What are the subdivision of signalling molecules?

A
  • Local chemical mediator
  • Hormone
  • Neurotransmitter
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6
Q

What are cell surface receptors?

A
  • When the signalling molecule is hydrophilic, it doesn’t have access to the inside of the cell.
  • So there are cell surface receptors that recognise the hydrophilic molecule and transducer a message into a signal within a cell.
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7
Q

What are intracellular receptors?

A
  • When the signalling molecule is are small hydrophobic it can pass diffuse through the membrane bilayer into the cell and the receptor is found within the cell.
  • Hydrophobic signalling molecule are carried in the blood on carrier proteins that’s released at target tissues.

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8
Q

What is a receptor?

A
  • A receptor is a molecule that specifically recognises second molecules or a family of molecules.
  • Ligand binding brings about regulation of cellular process.
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9
Q

What is a ligand?

A

A molecule that binds specifically to a receptor site.

  • Agonist: ligand that activates a receptor
  • Antagonist: a ligand may combine with receptor site without causing activation, as it opposes the action of an agonist.
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10
Q

What is the difference in binding affinity of receptors and enzymes?

A
  • Affinity of ligand binding is generally much higher than the binding of substrates and allosteric regulators to enzymes sites.

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11
Q

What are receptors classified by?

A

Classified according to:
- specific physiological signalling molecule (agonist) recognised.

Sub-Classification:
-Affinity (tightness of binding) of a series of antagonist.

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12
Q

What are the different types of acetylcholine receptors?

A
  • Nicotinic
  • Muscarinic (M1, M2, M3)

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13
Q

What is the difference between a receptor and an acceptor.

A

Receptor:

  • Silent at rest
  • Agonist binding stimulates a biological response

Acceptor:

  • Operate in absence of ligand
  • Ligand binding alone produce no response
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14
Q

What are the different signal transduction receptors?(from fastest response to slowest response)

A
  1. Membrane-bound receptors with integral ion channels (milliseconds).
  2. Membrane-bound receptors with integral enzyme activity
  3. Membrane-bound receptors which couple to effectors through transducing proteins
  4. Intracellular receptors - slowest response because the receptors are transcription factors and they have to go through the process of transcription and translation before the function is seen. (Hours or days)

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15
Q

What is the structure of a nicotinic acetylcholine receptor?

A
  • Pentameric complex
  • Two alpha subunits is the binding site for acetylcholine
  • The arrangement of the subunit allows for a pore to be in the centre of the molecule
  • A family of ligand gated ion channels
  • Ring of negative charge amino acids above and below the gate and allows cations to pass but not anions.
  • Binding leads to a conformational change that allows for potassium and sodium ions to pass through the channel.

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16
Q

What are the different membrane bound receptors with integral ion channels?

A

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17
Q

What are some of the structural components of the membrane bound receptor with integral enzyme activity?

A
  • Binding domain (extracellular)
  • Catalytic domain (intracellular )
  • receptors associated as diners
  • alpha helix which is highly hydrogen bonded and a rid like structure

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18
Q

What are different membrane-bound receptors with integral enzyme activity?

A

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19
Q

What is the mechanism of signalling via tyrosine kinase-linked receptors? ( first pathway)

A
  1. Agonist binds to the binding domain, cause autophophorylation of the catalytic domain.
  2. Autophosphorylation is phosphorylation by the receptor itself of its partnered subunit.
  3. The tyrosine phosphates (Y-P) can be recognised by specific binding sites on enzymes.
  4. Those enzymes can be activated directly by this or ore likely it can bring the enzyme up to the receptor where is can be phosphorylated and send off an activated phosphorylated enzyme into the cell.

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20
Q

What is the mechanism of signall8ng via tyrosine kinase-linked receptors? (Second pathway).

A
  1. Agonist binds to the binding domain, cause autophophorylation of the catalytic domain.
  2. Autophosphorylation is phosphorylation by the receptor itself of its partnered subunit.
  3. Alternatively and more common, between the enzyme and the receptor is a transducer. Which is a large protein that contains a number of tyrosine phosphorylation sites.
  4. So the transducing protein is phosphorylated by the activated receptor and then the the transducer can act as a docking site for multiple different enzymes, to bring the enzymes up to the receptor and activate those by tyrosine phosphorylation.
21
Q

How is the phosphotyrosine recognised on the receptor by the transducers and enzymes?

A
  • Y-P is recognised by src homologous domain
  • So the binding sites are called SH2 sites.

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22
Q

What is another group of tyrosine kinase linked receptors? And what are the different domains of the receptor?

A
  • The insulin receptors
  • Instead of being a dimeric receptor it is a tetrameric receptor with 2 alpha and 2 beta subunits.
  • Main difference is that post-translational disulphide links are formed between the alpha and beta subunits
  • Insulin domain
  • Transmembrane domain
  • Tyrosine kinase domain
23
Q

What are the features of membrane-bound receptors that signal through transducing proteins (7TMD) receptors?

A

• Coupled through GTP-binding regulatory proteins (G-proteins) to enzymes or channels

• Adrenaline binding to b-adrenoceptors activates the enzyme
adenylyl cyclase (ATP cAMP) via  a G-protein, Gs

• Acetylcholine binding to M2 muscarinic acetylcholine receptors stimulates K+ channel opening via a different G-protein, Gi

24
Q

What are the different domains of the G-protein coupled receptor?

A
  • Binding domain: Ligand binds to either N terminal region or within a cleft formed by folding of the 7 domains
  • G-protein coupling domain (intracellular side): agonist binding to the receptor changes the conformation of the receptor that clauses a change in this domain and activates the G-protein.

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25
Q

What type of protein is the the G-protein?

A
  • Heterotrimeric protein with G- alpha (s,I,q) and beta and gamma subunits.
  • When at rest the G alpha subunit is bound to GDP.

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26
Q

What happens when an agonist (adrenaline) binds to the GPCR?

A
  1. The GDP dissociates from the G alpha and is replaced by a GTP.
  2. This results in the dissociation of subunits to produce a G-alpha -GTP and a beta/gamma complex.
    - both of these complexes go on to activate an effector.

E.g. Gs alpha goes on to activate the enzyme adenylyl cyclase, which converts ATP to cAMP (secondary messenger in the cell).

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27
Q

What can target enzymes be susceptible to?

A
  • Stimulatory of inhibitory receptors.
  • The inhibitory receptor activates a different G protein called GI, this can send an inhibitory message to the target enzyme.
28
Q

What occurs in integrated signalling via G-protein coupled receptors?

A
  • So if the target enzyme is receiving both stimulatory and inhibitory signals from outside, what the system does is integrate those signals and produces a concerted response, balance integrated response at at the target energy.

• This adds a level of plasticity to the system such that different receptors within the same cell can integrate a response at the level of the target effector.

29
Q

What are the different domains of an intracellular receptor?

A
  • Binding domain (for agonist).
  • DNA binding domain (Zinc fingers).

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30
Q

How does the intracellular receptor exist at rest?

A
  • It exists as a receptor bound to an inhibitory protein complex.
  • So at rest the receptor is prevented from binding to DNA as the inhibitory protein complex is bound to the DNA binding site.

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31
Q

What happens when a steroid hormone (agonist) binds to the binding domain of the intracellular receptor?

A
  • The receptor undergoes a large conformational change
  • The inhibitory protein complex dissociates and the DNA binding site is then exposed, which can then go on to bind to DNA and affect transcription.

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32
Q

What are the different types of intracellular receptors and what is the difference between them?

A

Cortisol, oestrogen, Progesterone, Vitamin D, thyroid hormone and retinoids acid receptor.

They all have relatively the same DNA binding domains but different amino acid sequences.

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33
Q

What is the role of the GPCR in amplification in cellular signalling?

A
  1. Activated receptor, activated G protein to activate effector.
  2. If the receptor remains activated it can bind another G protein and activate it.
  3. It could activate 4 G-protein, 4 effector protein leading to amplification .
  4. E.g. activated effector could be an enzyme that converts ATP to cAMP and activate protein Kinase A, which could go on to phosphorylate thousands of substrate molecules.

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34
Q

What can response to receptor activation lead to?

A
  • It can lead to cellular activation or inhibition depending in the receptor activated.

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ICPP (9 decks)

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