2. Receptors Flashcards
Atenolol targets what? For what?
- B2 adrenoreceptors
- hypertension
Benzodiazepine targets what? For what?
- GABAa receptor (ion channel)
- anti-anxiety
Penicillin targets what? For what?
transpeptidase
- antibiotics
Probenecid targets what? For what?
- organic anion transporter (carrier)
- prolong penicillin action
What does a drug do at receptor targets?
- agonists activate receptor
- antagonists block action of agonist
What does a drug do at ion channel targets?
- either block
- or modulate the open/close of it
A benzodiazepine is given to ..
calm patients down
How does benzodiazepine work?
- anxious patients have too much chloride trandsuction
- benzo binds at an allosteric site near the GABA binding site
- to enhance effects of GABA
- when benzo and GABA act together, reduces chloride transduction and hyperpolarizes cell
What do drugs do at enzyme targets?
either inhibit or act as false substrate
How do NSAIDs work?
- immune activation, tissue damage etc damage phospholipids in the cell membrane
- this activates phospholipase A2 to work to produce arachidonic acid
- this with the work of cyclooxygenase forms prostaglandins (these cause inflammation, pain and fever)
- NSAIDs stop cyclooxygenase and prevent prostaglandin production
What do drugs do at carrier targets?
- transported in place of endogenous substrate
- inhibit transport
Define ‘receptor’
sensing elements in chemical communication systems that coordinate function of different body cells
Agonists … action of endogenous chemical messengers and antagonists … it
mimic
block
Define ‘agonist’
- a ligand (drug, neurotransmitter or hormone)
- that combines with receptors to elicit cellular response
Example of an agonist
- histamine
- acts as agonist at H1 receptor in smooth muscle
- increases local blood flow
Define ‘antagonist’
drug which blocks response to agonist
Example of an antagonist
- terfenadine
- antagonist at H1 receptors in smooth muscle
- decrease local blood flow
What does receptor sub-types mean?
- receptors within a family occur in different molecular varieties
- have similar structures but significant differences in pharmacological responses
How to identify receptor sub-types?
- on selectivity of agonists/antagonists (ligand binding assays)
- by cloning techniques
Give the subtypes of histamine receptor and what their agonist/antagonists are
- H1 ag is histamine, antag is terfendine
- H2 ag is histamine, antag is cimetidine
- H3 ag is histamine, antag is thioperamide
- H4 is same as above
How can receptor subtypes elicit different cellular effects?
- receptor with bound agonist is activated
- activated receptor has altered physical and chem proporties
- leads to changes within cell that cause biological response
4 receptor types that respond to drugs
- ligand gated ion channels
- G-protein coupled receptors
- enzyme/kinase linked receptors
- intracellular/nuclear receptors
Difference between ligand gated and voltage gated receptors
- ligand gated are channel linked receptors and require an agonist to open the channel
- voltage gated are not linked to receptors and require a change in electrical charge across a membrane to open/close
Example of a ligand gated receptor
- nicotinic acetylcholine receptor
- ACh causes skeletal muscle to contract by opening ligand-gated channels
Example of a voltage-gated receptor
- sodium ion channels in nerve cell membranes
- local anaesthetics work to block these
Nicotinic ion channel is what structure?
- pentamer of 5 subunits
- 2 alpha, a beta, a gamma and a delta
Resting vs active state of a nicotinic ion channel
- inside in resting is kinked and ion channel is closed
- when ligand or agonist binds to extracellular binding site, change in conformational shape
- twists around and opens kink to allow cations to go through
Clinical use of ACh antagonists
- in skeletal muscle, ACh acts on nicotinic receptor to cause muscle contraction
- nicotinic ACh receptor antagonists are muscle relaxants to allow surgical procedures
2 examples of G protein coupled receptors and what drugs work on them
- alpha/beta adrenoreceptors for epinephrine
- beta 2 adrenoreceptors for salbutamol
G protein coupled receptors are the smallest/largest receptors
How are they structured?
- largest
- single polypeptide chain with 7 transmembrane helices
- 3 subunits (alpha, beta and gamma)
G protein coupled receptors are slow/fast
- slower than others
- minutes
How is specificity of G-protein coupled receptors achieved?
- through molecular variation in alpha subunits
- Gs, Gi, Gq and G0
What does the Gs protein on G protein coupled receptors do?
- activates adenylyl cyclase
- activates calcium ion channels
What does the Gi protein on G protein coupled receptors do?
- inhibits adenylyl cyclase
- activates potassium ion channels
What does the Gq protein on G protein coupled receptors do?
activates phospholipase C
What does the Go protein on G protein coupled receptors do?
doesn’t have an alpha subunit
Explain Gs protein signal transduction
- unoccupied receptor doesn’t interact with Gs protein
- hormone or neurotransmitter binds to receptor
- occupied receptor changes shape and interacts with Gs protein
- Gs protein releases GDP and binds to GTP
- alpha subunit of Gs protein dissociates and activates adenylyl cyclase
- adenylyl cyclase catalyzes formation of cAMP
- when hormone is no longer present, receptor reverts to resting state
- GTP is hydrolysed to GDP and adenylyl cyclase is deactivated
All subunits of adrenoreceptors are activated by …
adrenaline or noradrenaline
Response in a particular cell of adrenoreceptor is dependent on …
which receptor subtype is expressed
What happens to adrenoreceptor alpha 1 when adding adrenaline?
- is the Gq form
- activates PLC
- get vasoconstriction
What happens to adrenoreceptor alpha 2 when adding adrenaline?
- is Gi form
- inhibits adenylyl cyclase
- auto-inhibition of neurotransmitter release
What happens to adrenoreceptor beta 2 when adding adrenaline?
- Gs form
- stimulate adenylyl cyclase
- bronchodilation
What happens to adrenoreceptor beta 1 when adding adrenaline?
- Gs form
- stimulates adenylyl cyclase
- accelerated heart rate
… is a beta 2 receptor agonist
salbutamol
… is a beta 1 receptor antagonist
atenolol
2 examples of kinase-linked receptors
- insulin receptor for insulin
- tyrosine kinase for imatinib
Structure of ‘kinase-linked receptors’
- large extracellular ligand binding domain connected to intracellular domain by single membrane-spanning helix
4 things formed by kinase-linked receptors
- receptor tyrosine kinase i.e insulin
- serine/threonine kinase
- cytokine
- guanylyl cyclase-linked
3 steps of kinase-linked receptors
- ligand binding
- dimerisation
- autophosphorylation
How do insulin binding receptors work as kinase-linked receptors?
- insulin binding activates receptor tyrosine kinase activity in intracellular domain of beta subunit of insulin receptor
- tyrosine residues of beta subunit are auto-phosphorylated
- receptor tyrosine kinase phosphorylates other proteins like insulin receptor substrates
- phosphorylated IRS promote activations of other protein kinases and phosphatases, leading to biologic actions of insulin
- for example lowered blood glucose levels
2 examples of nuclear receptors
- estrogen receptor for estradiol
- estrogen receptor for tamoxifen
Are nuclear receptors highly expressed?
- about 40 types so no
- heavily involved in kinetic reactions of drugs and interacts with gene transcription to increase proteinsynthesis
- but effects seen over months, years
Nuclear receptors are a family of … … receptors
48 soluble
2 classes of nuclear receptors
- class 1 (in cytoplasm, forming homodimers, ligands are endocrine - steroids, hormones)
- class 2 (in nucleus, form heterodimers, ligands are lipids - fatty acids)
Binding to … in nuclear receptors creates … changes
hormone response elements
Gene transcription changes - pos or neg
Explain nuclear receptor class 1 signal transduction
- unoccupied receptor doesn’t provide intracellular signal
- lipid soluble drug diffuses across cell membrane
- drug binds to receptor and occupied receptor changes shape and activates
- activated receptor moves to nucleus
- drug-receptor complex binds to chromatin, activating transcription of specific genes
- mRNA is translated into specific proteins resulting in specific biologic response
Most receptor operated channels have single/multiple binding sites. Explain
- multiple
- nACHR - heteromers 2 sites, homomers up to 5
- glycine Rs at least 4 sites
- binding at one site alters binding at another (pos or neg)
3 types of allosteric sites
- positive
- negative
- allosteric antagonists
4 types of orthosteric sites
- full and partial agonists
- inverse agonists
- reversible competitive antagonists
- irreversible competitive antagonists
2 effector regions
- non-competitive antagonists
- channel activators
