Receptors and membrane signalling Flashcards
What is meant by affinity?
KD =Binding strength
What is meant by efficacy?
Efficacy (Emax)- maximum response achievable
What is meant by a super-agonist?
Highly efficacious agonists - can produce a maximal response form the cell without binding to all of the availible receptors
- Emax- >100
- For example- goserelin (zoladex) is a super agonist of the gonadotrophin releasing hormone receptor. It suppresses production of the sex hormones, particularly in the treatment of brest and prostate cancer
What is meant by a partial agonist?
Low efficacy- cannot produce the cell’s maximal response, even when they have bound to all of the availible receptors
- Example- buprenorphine- opiod used to treat opiod addiction and pain
What are the 4 main drug receptors?
-
Enzymes
- Cyclooxygenase- aspirin receptor
-
Ion channels
- Ca2+channels bloacked by nifedipine
-
Transporters- pumps, transport proteins
- noradrenaline transporter blocked by cocaine
- “physiological” receptors
- receptors for hormones, neuroransmitters etc
- ACh, histamine, insulin etc
What are the other targets for drug action
- substrates, metabolites, proteins- asparagine
- DNA/RNA/ribosome- cisplatin
- targets of monoclonal antibodies -EGFR is targetted by cetuximab
- unknown mechanism
Give examples of drugs that have multiple targets
- Aspirin- inhibit COX1 and COX2, however. highly selective COX2 inihibitors may have unexpected side effects- tipping the balance of antithrombotic mediators in an unfavourable way
- Steroid hormones- bind to nuclear receptors and also membrane bound GPCRs
- Quetiapine- atypical antipsychotic- interacts with many different receptors- this means that different dose have completely different effects
What are the ways in which drugs alter cell function?
- alter membrane potential
- alter enzymes activity
- alter gene expression
- “hormone like”- e.g. glucocorticosteroids/ tyrosine
Some drugs may affect these directly- e.g. tetrodotoxin, aspirin, acridine dyes
However, most drugs affect cell function via physiological receptors
How are receptors classified?
- on the basis of the selective action of drugs
- named according to the transmitter or hormones with which they interact- e.g. acetylcholine receptors
- most hormones interact with more than one type of receptor
- subtle differences in protein structure underlie differences between subtypes
Give an example in which a transmitter acts on two different receptors.
Muscarinic ACh receptors become poisened by atropine
The low affinity nicotinic ACh receptors become visible- which increases blood pressure
What are the 5 Receptor superfamilies
- Integral ion channels
- Integral tyrosine kinases
- Steroid/nuclear receptors
- G protein coupled receptors
- Cystokine receptors
What is integral ion channel?
- 2 agonist bind to receptors
- causes opening of pore
- allows specific ion movement
- causes biological/ chemical change
e.g. nicotinic receptor, glycine receptor
What is Integral tyrosine kinase?
- Agonist binds
- Receptor dimerises
- Receptor autophosphorylates
- Receptor binds to intracellular proteins
- Kinase cascade which leads to gene transcription
e.g. insulin receptor
What is cytokine receptor?
- Agonist binds
- Receptor dimerises and Jak is activated
- Receptor and Jak becomes phosphorylated
- SH-2 domain protein (Stat) binds to receptor and becomes phosphorylated
- Stat dimerises which leads to gene transcription
e.g. prolactin receptor
What os Steroid/nuclear receptor?
- Agonist binds
- Receptor undergoes conformational change
- Receptor dimerises
- moves to nucleus and bind to response element
- increase RNA polymerase activity
- leads to production of specific mRNA
What is GPCR?
- Agonist binds
- Interacts with G protein
- Interacts with Effector
- Releases 2nd messenger
e.g. muscurinic receptors
