Y1S2W8 - Receptors Flashcards
State 4 objectives/challenges in communication of information?
- Causing the desired effect
- Timeliness - speed/time of delievry
- Imparting the correct information
- Reaching the right target/recipient
What type of molecule is a receptor?
Protein
examples of naturally occuring receptors?
Hormones, neurotransmitters and local chemical mediators (e.g. histamine)
Summary of Signal Transduction?
Transmission of molecular signals from a cell’s exterior to its interior.
Surface receptor proteins bind ligands, resulting in conformational changes which allows for chemical signal to be ‘read’ within the cell.
Purpose of extra-cellular recipients? What is the need?
Water soluble/polar and endogenous signalling molecules cannot diffuse across membranes (fatty/non-polar) - they bind to receptor proteins on the SURFACE
Intracellular proteins?
Hydrophobic drugs can cross membrane and bind to receptors within the cell to have effect.
Two classifications of receptor proteins?
- Pharmacological Classification - nature of drug/ligand
2. Signal Transduction Pathway/Structural Classification - 3D structure
What is a G-Protein Linked/Coupled Receptor? (GPCR’S)
Largest, most diverse group of membrane
surface receptors
G protein is not a receptor, protein joins with a receptor to ‘work’
Where are GPCR’s involved?
vision, smell, behaviour, mood, immune system, inflammation, autonomic nervous system
Structure of G-protein linked/coupled receptor?
Folded within a cell membrane.
7 transmembrane (TM) sections - hydrophobic and helical
Numbered I-VII from N terminal
3 subunits
Intra and extra cellular loops
G-protein binding region
Extracellular amine group
How G-Proteins work/Signal Transduction Pathway
- Chemical messenger binds to receptor leading to complete change of shape
- This opens binding site so G-protein can interact
- Once bound, g-protein subunits fragments
- subunit travels through membrane and binds to allosteric site of enzyme
- Enzyme alters shape and opens active site which causes reaction
Relevance to pharmacy?
use?
30-40% drugs are GPCR’s
They are a good drug target
Used in heart disease, cancer, diabetes, depression arthritis
Only 10% of GPCR’s are known drug targets - huge research focus
What are the GPCR subunits?
alpha, beta and gamma
Which molecules are bound to G protein? Importance?
GDP and GTP - guanyl di/tri-phosphate
When phosphate is added/removed something is happening/stopping
Roles of GDP/GTP
When G-Protein binds the shape changes, GDP is removed and GTP is added (increase in phosphate therefore something going to happen)
When GTP binds shape changes and subunits break off and leave the receptor
What happens after trasnduction pathway?
ALPHA subunit catalyses formation of cyclic AMP - secondary messenger that carries signal to cytoplasm
cAMP activates protein kinase A which increases phosphorylation in specific proteins and leads to biological effect
How is the signal stopped?
Alpha subunit has intrinsic GTPase which breaks down phosphate, converting GTP-GDP
Subunits reform the G-protein and stops the signal tranmitting
How is the signal stopped?
Alpha subunit has intrinsic GTPase which breaks down phosphate, converting GTP-GDP
Subunits reform the G-protein and stops the signal transmitting
What are agonists/antagonists?
agonist - encourages
antagonist - inhibits
What is a ligand gated ion channel?
Transmembrane channel which allows passage of polar molecules/IONS e.g. K+/Na+
Lock/gate/induced fit mechanism - opens in response to messenger e.g. neurotransmitter
Allows passage of large number of ions - very efficient - FAST
Receptor structure in ion channels
- 5 protein subunits
- Glycoproteins
- Traverse the membrane
- Binding site
- Specific cationic/anionic channels
- Classified by number of transmembrane domains e.g. 4-TM (joined by loops)
Ion channel link to pharmacy
Many diseases caused by dysfunction of ion channels -
Can be genetic
e.g. cystic fibrosis, epilepsy, cancer etc.
Non-genetic
e.g. toxins stopping channels working properly
Drug classes that alter ion channels
- Local anaesthetic
2. Benzodiazepines
Tyrosine Kinase Receptor?
Receptor with many tyrosine kinase residues
Activates enzymes directly (does not require a protein) - activated by cytokines (inflammatory response)
Important target for anti-cancer drugs
Structure of TKR?
Transmembrane unit
Single extracellular region (N-terminal) - site for messenger
Single intracellular region - enzyme (C-terminal)
How does TKR work?
Resting/active state
Rests until ligand binds, changing shape to reveal active site on C-Terminus (phosphorylation of tyrosine residues can occur)
Example of TK receptor (target for cancer drug)
Receptor for Epidermal Growth Factor (EGF)
EGF is bivalent - can bind to 2 receptors at once: very efficient
How do intracellular receptors work?
hydrophobic messenger binds to receptor and complex moves into cell - often bind to DNA
Induced fit - change of shape - dimerisation, binds to coactivitor - whole complex binds to DNA region
Receptor is found within the cell
Intracellular receptor structure?
Non-membrane bound
Single protein containing ligand binding site and DNA binding site
DNA binding site/Zinc fingers = able to identify specific nucleotide sequence
Famous example of intra-receptor and drug
Oestradiol/oestrogen - oestradiol crosses membrane and binds to oestrogen receptor - change of shape
process follows leading to binding to DNA, switches on transcription gene which leads to protein synthesis
Drug: TAMOXIFEN
inhibits receptor to prevent tumour growth
