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A Pharmacology L2 > Lecture 9 - receptor and drug action > Flashcards

Lecture 9 - receptor and drug action Flashcards

1
Q

What are the functions of receptors?

A
  • recognise stimulus
  • transfer stimulus into cell
  • amplification of cytoplasmic signal
  • modulation of effector systems over time
  • adaption of the system through
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2
Q

What does selective expression of certain receptors and molecules involve?

A

Involved in signal transduction allow cells to respond specifically to particular stimuli

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3
Q

How do drugs work through receptors?

A

They exploit their function to modulate the function of specific cells in the tissues where the receptors are expressed

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4
Q

What allows you to make testable predictions of signal transduction mechanisms?

A

The class/structure of receptors

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5
Q

What are the 4 receptor families?

A

Type 1 - ligand gate ion channels (ionotropic receptors)
Type 2 - G-protein coupled receptors (metabotropic)
Type 3 - kinase-linked
Type 4 - Nuclear receptor

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6
Q

Describe Type 1- ligand gated ion channels (ionotropic receptors)

A

Proteins are embedded in plasma membrane. Receptors targeted will usually have a ligand binding site facing the outside. These receptors are ion channels - agonist binds leading to the opening of the channel. It takes multiple proteins to make up the ion channel.

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7
Q

Describe Type 2 - G-protein coupled receptors (metabotropic)

A
  • 30% of therapeutically useful drugs target GPCRs (metabotropic)
  • 7 transmembrane domains, anchored to plasma membrane.
  • Ligand binding site facing outside.
  • Intracellular side interacts with G-proteins
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8
Q

Describe Type 3 - kinase-linked receptors

A
  • anchored in membrane (only 1 transmembrane domain)
  • Ligand binding site is facing outside
  • Intracellular side, protein contains kinase (kinase phosphorylate protein)
  • Enzymatic domain built into protein
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9
Q

Describe Type 4 - Nuclear receptor

A
  • Missing transmembrane domain - not embedded in plasma membrane - found inside cell.
  • Either in cytoplasm or nucleus
  • For any ligand to reach binding site on nuclear receptor, it needs to enter cell first.
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10
Q

What do all receptors contain?

A
  • DNA binding domain
  • all have a binding site
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11
Q

Describe the timing of events

A

Ligand - fastest (just open channel - millisecond)
GPCR - need to activate G-proteins - 100 milliseconds
Kinase - signalling takes minutes to hours
Nuclear - changes of gene transcription, therefore takes hours

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12
Q

What receptors are for acetylcholine?

A

Ionotropic & metabotropic receptors - identity of stimulus doesn’t give us information about receptor

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13
Q

What is the basic mechanism of Type 1 - ligand gated ion channels?

A

Channel gating is controlled by ligand-binding, which brings about conformational change, which opens pore to let ions flow. Which ions are determined by structure of pore - e.g. depending on size and charges of ions.
- determined by concentration gradient & charge

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14
Q

What is an example of a drug which binds to a ligand-gated ion channel?

A

Nicotine acts at the Nicotine Acetylcholine Receptor. Reward center contain nicotinic receptors, which leads to the release of dopamine when activated.

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15
Q

Explain how molecular architecture of ligand-gated ion channels identifies distinct families

A

Proteins in nicotinic receptors have conserved structure. A single protein that is present will have 4 transmembrane domains, one of which that creates selectivity.

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16
Q

What do anions do?

A

Negatively charged (gained an electron) - hyperpolarization

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17
Q

What do cations do?

A

Positively charged (lost an electron) depolarization and excitation of neuron

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18
Q

Describe the structure of a nAChR

A

nAChR - nicotinic acetylcholiine receptor
- pentameric assembly
- Nicotinic receptors are cation receptors - sodium, potassium & calcium

19
Q

What type of receptors are GABAa receptors?

A

Anion receptor - chloride

20
Q

Describe the features of 5HT3 receptors (serotonin-ligand gated ion channel)

A
  • 2nd transmembrane domain has a negative charge and therefore cation selective
21
Q

What does knowledge of channel permeability and gating properties allow?

A

Allows for insight to functional consequences of their activation

22
Q

What is P2X gated by?

A

Extracellular ATP - 2 transmembrane domains - 3 proteins come together to make functional channel

23
Q

Describe Calcium type release

A

Could rely on the presence of a secondary messenger - e.g. IP3

24
Q

Describe an ionotropic glutamate type

A

NMDA - 3 transmembrane domains with re-entrance loop, which creates the pore. 4 proteins need to come together to make the functional channel - tetrameric assembly

25
Q

What does complexity provide?

A

Diversity and opportunity for drug targeting

26
Q

Where can nicotinic receptors be found?

A

Nicotinic receptors are pentameric and can be found in skeletal muscle

27
Q

Describe features of GPCRs

A

Made up from a single protein that crosses the membrane 7 times. Activation of receptor (binding of agonist), leads to activation of G-protein leading to signal transduction

28
Q

What type of receptor does Cannabis target?

A

Cannabis target GPCRs - 2 cannabinoid receptors - CB1 & CB2

29
Q

What has genome sequencing identified about GPCRs?

A

GPCRs - genome sequencing has identified >800 of these receptors by their conserved structure. Many GPCRs are involved in sensing the environment, chemical communication and homeostatic mechanisms.

30
Q

What is ‘canonical’ signalling by GPCRs?

A

Binding of agonist leads to activation of G-protein. Association between alpha subunit and receptor. Alpha subunit changes affinity for guanine nucleotide. Lowers affinity for GDP and raises its affinity for GTP. When alpha subunit has GTP bound, its affinity for beta gamma subunit decreases. The beta gamma subunit may lead to downstream effects. This may include interacting with another protein. Alpha subunit is a GTPase, meaning eventually it will cleave GTP into GDP. This will lead to it raising its affinity for beta gamma subunit and they will come together and stop signalling. Removal of ligand will also terminate signalling

31
Q

How many types of alpha subunits that code for proteins are there?

A

13 types of alpha subunits - named by their G-alpha subunit

  • G-alpha-s (stimulates activity of adenylyl cyclase)
  • G-alpha-q (activates phospholipase C)
  • G-alpha-i (inhibits activity of adenylyl cyclase)

Acting through G-proteins, controls the production of secondary messengers.

Protein Kinases - e.g. PKA

32
Q

Describe the pathway of G-proteins

A

G-proteins –> target enzymes –> secondary messengers –> protein kinases –> effectors

33
Q

What are examples of target enzymes?

A
  • Adenylyl cyclase
  • Phospholipase C
34
Q

What are examples of second messengers

A
  • cGMP
  • cAMP
  • IP3
  • DAG
35
Q

What are examples of protein kinases?

A
  • PKG
  • PKA
  • PKC

Protein Kinase G/A/C

36
Q

What are examples of effectors?

A
  • Enzymes, transport proteins, etc.
  • Contractile proteins
  • Ion channels
37
Q

Explain how Type 3 receptors - receptor tyrosine kinases - function

A

They will cause phosphorylation of tyrosine residues. Types of receptors include GFs (growth factors), as well as insulin. Control proliferation and cell growth, as well as controlling metabolism. Activation of receptors requires 2 molecules to come together.

38
Q

Describe how tyrosine kinase receptors interact

A

2 receptors of same type, occupied by an agonist, are brought together (physically) when ligand is bound.

This leads to the kinase domain on one subunit phosphorylating its neighbour & vice versa - AUTOPHOSPHORYLATION - creates binding sites for downstream effector molecules, which ultimately will lead to changes in the cell - e.g. changes in gene transcription.

39
Q

How are cytokine receptors and tyrosine kinase linked receptors?

A

Kinase domain isn’t encoded in receptor protein itself, but another separate molecule that is tightly associated with the receptor - however the signalling pathway is very similar.

40
Q

Explain what happens when receptor and molecule come together

A

They cross-phosphorylate each other on tyrosine residues, leading to change in transcription

41
Q

Describe features of Type 4 receptors - nuclear receptors

A
  • Not bound to membrane but found inside cell
  • Class 1 receptors - homodimers (2 proteins of same type come together to make receptor. Ligand can bind then move into nucleus
  • Class 2 receptors - heterodimers (made up of 2 different proteins - e.g. thyroid receptors) They live inside nucleus already. Agonist leads to changes in gene transcription.
42
Q

What % of drugs target nuclear receptors?

A

10%

43
Q

What do PXR detect?

A

Xenobiotics - i.e. foreign molecules, induce drug metabolizing enzyme e.g. CYP3A metabolizes approx. 60% of prescription drugs.

44
Q

How are receptors can lead to disease

A

Autoimmune disease - antibodies to receptors, leading to loss of function of that receptors

Mutations - e.g. in growth factor receptors can lead to cancer

A Pharmacology L2 (15 decks)

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