Session 6 - Receptors and membrane turnover Flashcards
Does a molecules only fall into one category of function?
-No it can be multiple
In what two ways can intercellular signalling occur?
- Secreted molecules
- PM-bound molecules
What is paracrine signalling?
-Cells secrete local chemical mediators to communicate with other local cells
What is endocrine signalling?
-Hormones released into the blood stream and effect a distal target tissue
Why do hydrophilic molecules have to act through surface receptors?
-Cannot cross membrane
What is meant by a receptor being functionally silent?
-The receptor is in its unbound state, having no effect on the cell
What is an agonist?
-A ligand which produces activation of a receptor
What is an antagonist?
-A ligand which does not cause activation when it binds to the receptor and prevents an agonist binding
What is a partial agonist?
-An agonist which does not generate maximum cellular response
What is an acceptor?
-A receptor which operates in the absence of a ligand, however it is regulated by the ligands which do bind to it
Which binding has a higher affinity, enzyme-substrate or receptor-ligand?
-Receptor-ligand
How are receptors classified?
-1st based on the specific ligands they bind
-Subclassified based on the affinity of a series of agonists and antagonist they bind
eg classification -> acetylcholine receptors
Agonist -> nicotinic (nicotine agonist)/muscarinic (muscarine)
Antagonist -> M1/M2/M3 in order of affinity for antagonist
What are super-families?
-A large group of receptors which all share the same basic structure
In what 4 ways does transduction of an extracellular signal occur involving receptors?
1) Membrane bound receptors with integral ion channels
2) Membrane bound receptors with integral enzyme activity
3) Membrane bound receptors which couple to G-proteins
4) Intracellular receptors
What type of receptors are membrane bound receptors with integral ion channels?
- Ligand-gated channels
- Voltage-gated channels
Why are ‘classical’ ligand-gated ion channels a superfamily?
- They have similar pentameric structures, with each subunit having 4 TMD
- One TMD forms the pore which has 2+ve/-ve charges on it making it cation/anion selective
Name some ‘classical’ ligand-gated ion channels
- NachR
- GABA R
- Glycine R
- Glutamate receptor
Why are some ligand-gated channels ‘non-classical’?
-Structurally distinct from other ligand-gated ion channels
Name some ‘non-classical’ ion channels
- ATP-sensitive K channel
- IP3 receptor
- Ryanodine receptor
How do ligand-gated intergral ion channel receptors work?
- Ligand binds to receptor
- Conformational change
- Gated channel opens
How does an membrane bound receptor with integral enzyme activity work?
- Agonist binds causing conformational change
- Activates intrinsic enzyme activity
Give an example of a group of membrane-bound receptors with intrinsic enzymatic activity
-Tyrosine kinase receptors
How do receptor tyrosine kinases work?
- Agonist binds causing receptor dimerisation and activation of a protein kinase in the cytoplasmic domains of the receptors
- Receptors autophosphorylates tyrosine residues on the opposite dimerised receptor
- Phosphorylated tyrosines are either recognised directly by enzymes or by transducing proteins
- The effector enzymes then become allosterically activated -> transducing the message to the intracellular environment
What must effector enzymes have to directly recognise phosphotyrosine residues on RTK?
-SRC-homology-2 domains (Phosphotyrosine recognition sites)
Give an example of a receptor tyrosine kinase
-Growth factor receptors (EGFR, PDGFR)
What is a G-protein?
-GTP-binding regulatory proteins
How many transmembrane domains do GPCRs have?
-7
How are chemical signals classified based on function?
- Hormones; signalling between different tissues via the circulation
- Neurotransmitters; signalling at specialised cell junctions
- Local chemical mediators; signalling between adjacent cells in the same tissue
What are the possible effector enzymes of GPCRs?
- Adenyl cyclase
- Phospholipase C
- Ion channels
Give examples of GPCRs
- Muscarinic Ach
- Adrenoreceptors
- Dopamine receptors
What type of molecules use intracelluar receptors?
-Hydrophobic
eg steroid hormones, thyroid hormones
Where are the intracellular receptors in the resting state?
-Bound to hsp for stability in the cytoplasm
What happens to an intracellular receptor when an agonist binds?
- Activated receptor dissociates from hsp/chaperone and the receptor:agonist translocates to the nucleus
- Conformational change occurs to expose DNA binding domain of receptor
- Receptor binds and regulates gene transcription
Why does amplification of a signal produced by an extracellular ligand have to occur?
-The concentration of extracellular ligand binding is relatively low, so if order to produce the maximal response the signal has to be amplified
How does amplification of a signal occur?
-The activation of one enzyme can modify multiple target enzymes beginning a cascade
Give an example where agonist binding inhibits a target effector rather than activates it
- In cardiac pacemaker cells ach acting on M2 receptors decreases the HR
- In hepatocytes, glucagon stimulates glycogen breakdown
