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Introduction to medicine (Year 1) > Receptor basics and mechanisms > Flashcards

Receptor basics and mechanisms Flashcards

1
Q

What is tissue selectivity?

A

Certain tissues exhibit certain receptors, hence why different drugs disproportionately affect different tissues

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2
Q

What is chemical sensitivity?

A

Only specific drug structures bind to receptors

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3
Q

What is amplification?

A

Small number of drug/receptor interactions initiate significant biological effects

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4
Q

Define agonist

A

Drug which binds to a receptor to produce a biology cellular response, therefore have affinity and efficacy

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5
Q

Define antagonist

A

Drug which binds to a receptor but does not produce a biological cellular response- antagonists bind to receptors and prevent agonists producing effects, therefore these only have affinity

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6
Q

Define affinity

A

The extent or fraction to which a drug binds to receptors at any given drug concentration

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7
Q

Define efficacy

A

Ability to initiate a physiological response through interaction with the receptor

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8
Q

Is binding to receptors reversible or irreversible?

A

Reversible, as most agonists and antagonists bind reversibly, as their they bind to their receptor and then dissociate from it

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9
Q

What is KA?

A
  • Measures affinity
  • KA is the affinity at equilibrium, and assesses the affinity of an agonist to a receptor
  • Every drug has its own KA value
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10
Q

What does a smaller KA mean?

A
  • The agonist has a greater affinity for a receptor than a drug with a higher KA value. This is because the KA value will show fewer free receptors, meaning most are bound to a agonist-receptor complex.
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11
Q

What is EC50?

A
  • Measures efficacy
  • Half maximal effective concentration, describes how well an agonist produces an action assessed by the effective concentration producing 50% of a maximal response.
  • Assesses how well an agonist produces an action.
  • This value can be used to compare drug potency
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12
Q

What is drug potency determined by?

A
  • Affinity and Efficacy
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13
Q

Affinity (KA) and efficacy (EC50) of an agonist are not…?

A

Equal, as you don’t need full occupancy of receptors to produce a maximum response

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14
Q

Why don’t receptors need to be full to produce a maximum response?

A
  • This is because receptors amplify signals, so only a small number of drug receptor interactions produce biological effect, hence why drugs work at such low concentrations
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15
Q

What is the effect of competitive antagonism on concentration-response curves?

A

Antagonist binds to and competes at the same site as the agonist, as both antagonist and agonist compete for the same receptor binding site

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16
Q

What are receptors?

A
  • Molecular structures (mainly proteins) that receive input and produce an effect through activation of single transduction pathways
  • Are associated with the plasma-membrane and permit communication between the outside and inside of a cell- although some are found inside the cell
  • Receptors recognise endogenous chemicals (naturally occurring such as neurotransmitters) and also recognise and bind to drugs
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17
Q

What happens when a chemical signal reaches a receptor

A
  • Chemical signal binds to receptor
  • This causes a change in receptor protein conformation
  • Signal transduction
  • Cellular response
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18
Q

What are the 4 types of receptors?

A
  • Ligand- gated receptors
  • G-protein coupled receptors (GPCRs)
  • Tyrosine kinose receptors
  • Intracellular/ nuclear receptors
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19
Q

What happens when an agonist binds to a receptor?

A

It produces an agonist receptor reaction, leading to a conformation change in receptor allowing it to initiate a biological response in the cell.

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20
Q

What bonds can drugs form with receptors?

A
  • Hydrogen bonding
  • Ionic bonding
  • Van der Waal’s forces (London forces)
  • Covalent bonding
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21
Q

What bonds allow for easier reversible binding and good dissociation and why?

A

Hydrogen, ionic and van der waal’s due to their forces being relatively weak

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22
Q

What bond leads to irreversible binding and poor dissociation?

A

Covalent bonding due to its strong stable bonds

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23
Q

What is the name given to the molecule formed when an agonist or antagonist binds to a receptor?

A

Agonist/antagonist receptor complex

24
Q

What happens if there are low levels of agonist or antagonist but lots of receptors?

A
  • There will be few agonist/antagonist complexes, therefore reaction rate towards the complexes (right) is limited
25
Q

Why will reaction rate eventually reduce?

A
  • The number of receptors is finite, there’s a limit to the number of agonist/antagonist receptor complexes
26
Q

What are the 4 receptor families?

A
  • Ligand-gated receptors
  • G-protein-coupled receptors
  • Tyrosine kinase receptors
  • Intracellular receptors
27
Q

What are ligand-gated receptors?

A
  • A class of integral membrane proteins- they form a membrane ion channel to permit the passage of select ions (e.g. Na+/K+).
  • Produces a very fast response, in a matter of milliseconds, so is essential for fast communication, such as muscle movement.
28
Q

What is a ligand?

A
  • A molecule that binds to a receptor (or another molecule), usually a neurotransmitter, hormone etc.
29
Q

What are properties all membrane receptors have in common?

A
  • Trans-membrane (integral proteins)
30
Q

What are trans-membrane proteins?

A
  • Amino acids that are hydrophobic, sitting in plasma membrane
  • Other areas of the protein are hydrophilic (fine with aqueous environments) and so sit on the outside/inside of the cell
31
Q

What are the structural features of ligand-gated receptors?

A
  • 5 protein subunits
  • Subunits form an ion channel
  • N-terminal- this is ligand binding site and there’s a binding site on each of the 5 subunits
  • Extracellular site
    An example of a ligand gated receptor is nicotinic receptors
32
Q

What is the signal transduction mechanism of ligand-gated receptors?

A
  • Ligand binds to receptor
  • Conformation change in subunits
  • Ion channel opens as a pore opens between the subunits, allowing the ions to flow and so there’s an increased ion flux as ions move down the concentration gradient
  • Change in cell excitability
33
Q

What are G protein coupled receptors (GPCRs)?

A
  • A class of integral membrane proteins, represent the largest and most diverse class of receptors
  • Produce slower response than ligand-gated, takes seconds to minutes. E.g. heart rate increases, but doesn’t happen instantly
34
Q

What are the structural features of GPCRs?

A
  • 1 single protein
  • 7 transmembrane regions
  • An N-terminal- ligand-binding site-
  • A C- terminal- G protein binding site
35
Q

What is the signal transduction mechanism for GPCRs?

A
  • Ligand binds to receptor
  • Activation of G-proteins
  • Production of intracellular messengers
  • Cellular function
36
Q

What are tyrosine kinase receptors?

A
  • Class of cell-surface proteins- characterised by their cytoplasmic region’s intrinsic tyrosine kinase activity
  • Slow response- can take minutes, hours or days, example is insulin binding to insulin receptors
37
Q

What are the structural features of tyrosine kinase receptors?

A
  • 1 single protein subunit
  • 1 transmembrane domain (these are regions of a protein that are hydrophobic)
  • N-terminal- ligand-binding site
  • C-terminal- effector binding site
38
Q

What is the signal transduction mechanism of tyrosine kinase receptors?

A
  • Ligand binding to monomers induces dimersiation -> monomers become 2, allows phosphorylation
  • Monomers phosphorylate tyrosine residue in each other
  • Phosphorylated intracellular domains bind cellular proteins
  • Cellular function
39
Q

What are intracellular/nuclear receptors?

A

A class of intracellular proteins characterised by their intracellular location

These have the slowest response, being hours, days, months or longer

40
Q

Explain the importance of phosphorylation in the tyrosine kinase receptor transduction pathway

A
  • Tyrosine kinase puts a phosphate group on an adjacent tyrosine phosphate
  • This causes an area to be the phosphorylated region which allows the binding of cellular proteins
41
Q

What are the structural features of intracellular receptors?

A
  • Receptor found within cytoplasm of cell- can easily gain entrance to cell
  • 1 single protein subunit
  • DNA binding site - When activated goes to nucleus + bind to gene in DNA, then C-terminal helps control it.
  • N-terminal- binds heat shock protein HSP - binds when ligand bind to but isn’t active
  • C- terminal- controls transcription
    An example of intracellular receptors is the steroid hormone
42
Q

What is the signal transduction mechanism of intracellular receptors?

A
  • Ligand (drug, hormone) crosses plasma membrane
  • Hormones displaces HSP and binds to N-terminal
  • Hormone/ receptor complex enters nucleus and binds to hormone-responsive-element on gene
  • Alters gene transcription
43
Q

What are G proteins?

A

Guanine nucleotide (GTP/GDP) binding proteins comprised of three subunits (alpha, beta, gamma)

The beta and gamma units allow the protein into the membrane

44
Q

Describe the cyclic activity of drug-receptor binding produced by G-proteins

A
  • When no drug (ligand) is bound- G protein (alpha, beta and gamma) is bound to receptor, GDP is bound to the alpha subunit
  • The drug binds to its g-protein coupled receptor
  • There is a change in receptor (G-protein) conformation
  • GTP now binds to G alpha subunit. This is because change in interactions (due to drug binding) between G-protein and receptor leads to opening that allows GTP to come in. GTP has higher affinity to alpha subunit than GDP.
  • G alpha subunit dissociates from receptor to induce a cellular response
  • Intrinsic G alpha subunit has GTPase activity- GTP dephosphorylates to GDP and G-protein, causes alpha, beta and gamma subunits to re-associate and bind with unbound receptor, going back to resting state
45
Q

What are the different sub-types of the G- alpha subunits?

A

G- alpha s
G -alpha i
G- alpha q

These are the intracellular responses that occur after the G-alpha has dissociated

46
Q

What do these different alpha subunits do?

A
  • Interact with specific targets including the enzymes adenylate cyclase (AC) and phospholipase C (PLC). These are the 2 main targets of the alpha subunit pathways.
47
Q

Describe the function of Gs

A

Stimulates adneylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP)

48
Q

What is cAMP?

A
  • An intracellular messenger
49
Q

Describe the function of Gi

A

Inhibits adenylyl cyclase, which will then inhibit the conversion of ATP to cAMP, decreasing cAMP levels

50
Q

Describe the function of Gq

A
  • Stimulates phospholipase C, which cleaves (hydrolyses) PIP2 (plasma membrane phospholipid) in the cell membrane into IP3 (water soluble) - IP3 acts inside cell to stimulate action of IP3 receptor (a ligand-gated receptor) and calcium moves into the cytosol, within aqueous part of membrane to activate contractile mechanisms - and DAG (triglyceride) - DAG activate PKC (protein kinase C) that modulates calcium levels and contraction
51
Q

How does IP3 increase calcium levels in cytosol?

A
  • Acts at own receptor inside cell found on calcium stores in sarcoplasmic reticulum, which is ligand-gated, so when activated pores open, allows calcium influx inside cell
52
Q

What are DAG, IP3 and cAMP?

A

Intracellular messengers, they trigger signalling cascades that lead to cellular functions and underlying changes to physiological processes

53
Q

What is the G protein cycle?

A
  • Consists of a G protein-coupled receptor (GPCR) activating the G protein by promoting the exchange of GTP for GDP, which allows the alpha, beta and gamma subunits to separate and activate downstream targets
54
Q

What are the properties of G-protein-coupled-receptors?

A
  • 1 single protein
  • 7 transmembrane regions ( this is where proteins traverse )
  • N-terminal - ligand-binding site, outside the cell
  • C- terminal- G-protein binding site, inside the cell
  • G-protein coupling region- where G proteins bind
55
Q

What is the signal transduction mechanism of GPCRs?

A
  • Ligand binds to receptor
  • G-proteins activated
  • Intracellular messengers produced
  • Cellular function

Introduction to medicine (Year 1) (24 decks)

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