Lec 2- receptor Flashcards

Question

G-Protein Coupled Receptors

Answer 1

STRUCTURE: 7 transmembrane helixes back and forth through the membranes - The largest family of integral membrane protein, integral protein = is a protein that passes all the way through a membrane - They recognise a large range of ligands e.g. proteins, lipids, amino acid, photons (light) - GPCR's work by activating a G-protein via transduction (hence 2ndary messenger) and beta-arrestin (they tend to activate protein kinase and cell desensitisation) - Share a common architecture (GPCRs are also referred to as 7-TM receptors)

Answer 2

- LARGE LIGANDS: make contact with extracellular regions - SMALL LIGANDS: Sit in the hydrophilic pocket within the transmembrane helices e.g. ACh or NA

Answer 3

- Ionic interaction (full +ve and -ve charge)- this is long range, non-directional (non-specific, drug can be in any rotation) and strong interaction - Hydrogen bonds between -OH and (-NH₂ ), medium range, fairly weak bonds individually but collectively is stronger, Directional- has to be in a straight line (this gives more specificity) - Hydrophobic interactions- between uncharged amino acids, short range, non-directional: ALTHOUGH- important in specificity because if a hydrophobic molecule is next to the hydrophilic pocket this could cause repulsion and so change the way drugs bind

Answer 4

- STERIC FACTORS: basically the shape of the drug and the shape of the receptor have to be similar to allow the ligand to dock; short range but very important in specificity e.g. very big drug in a small receptor pocket - Lock and key model AND induced fit model (both right but induced fit is more applicable)

Answer 5

- Look at notes for the picture - It won't fit into the binding site of the muscarinic receptors because of the hydrogen bonding and hydrophobic interaction arent there - NH3+ group forms an ionic bond with TM3 (transmembrane protein 3)- long range pull - There are 3 OH groups: the 2 on the benzene ring form H binds with TM5; the OH on the aliphatic chain forms an H bond with TM7 - The benzene ring forms 2 hydrophilic bonds with TM6 and 7

Answer 6

1) agonist binds to receptor causing flowering 2) Agonist alters receptor state- this is accompanied by a conformational change - This is usually accompanied by a conformational change in the receptor - TM5,6,7 movement has been noted in the cytoplasmic face of GPCRs 'flower effect' - Governed by a multiple molecular switches

Answer 7

- If a receptor is treated for too long (agonist is bound) with high conc of agonist the response fades away. DESENSITIZATION: stops receptor being over activated - During desensitisation, receptor uncouples from G-protein and is internalised (moved into the cell)- During this process, the G-protein falls off and beta-arrestin binds instead; B-arrestin then drags into the cell; the receptor can signal in a different way when attached to beta-arrestin - Desensitisation is caused by specific protein kinases called G-protein coupled receptor kinases (GRK's).

Answer 8

- This leads to binding of arrestin to block G-protein binding and switching signalling to phosphorylation (MAPK) - Phosphorylation involved in G-protein-coupled desensitisation - 3rd or 4th loop are phosphorylated on the receptor (c-terminal) this is where B-arrestin associates - Phosphorylated by GRK's

Answer 9

- FAMILY A: (usually) small N-terminals- most common e.g. muscarinic receptors; Histamine receptors - FAMILY B: medium-sized terminals- these bind peptide hormones e.g. glucagon; corticotropin - FAMILY C: Large N terminus- bind small ligands e.g. GABA, n Ca²⁺

Answer 10

-Be careful GPCR's and G-protein are different ## Footnote - Trimeric peripheral membrane proteins - Relay signal from GPCR's to 2nd messenger producing enzymes and ion channels - Activated by GTP/GDP exchange - B+Y always stay together and always attached to the plasma membrane - a- always stays attached to the membrane but not always associated w/B+y units this is determined by whether a- is bound to GTP or GDP exchanged

Answer 11

- When GDP is bound the a-subunit is inactive and associated wBeta and gamma units (trimeric G-protein) - When activated the GDP- falls off and GTP attaches which signals to the G-protein to become active - The alpha then separate and they can go and activate other proteins - This process is catalysed by the GPCR's

Answer 12

- GPCR binds to inactive trimeric G-protein (Alpha GDP beta gamma) see BB replay - The Alpha subunit binds (has a finger-like part which sticks into the GPCR), as the finger moves up it nudges another part of the Alpha unit which removes GDP off the unit, allowing GTP to bind - This is switched off because a-subunit can act as an enzyme and convert GTP --\> GDP - This causes the a-unit to become inactive and causes high affinity for beta and gamma units and makes them inactive

Answer 13

- 20 a-sub units; 5 b-units and 12 y-units - Individual receptors have a strong preference for a combination of particular subunits - a-subunit seem to take a primary role in activating effector - B and Y subunits can also activate or modulate the activity of a wide range of effectors such as adenylate cyclase, phospholipase C, ion channels - This gives a wide range of action

Answer 14

- alpha s: activates adenylate cyclase, Ca²⁺ channels, activated by cholera toxin (stimulatory) - Alpha i: inhibit adenylate cyclase, open K⁺ channels (nerve inhibited) or close Ca2+ or inhibit pertussis toxin-outside nerve system - Alpha O: inhibit adenylate cyclase, close Ca²⁺ channels- inside nerve systems - Alpha q: activate phospholipase - Alpha 12,13: activate shape change (motile cells by activating kinases) also links to MAP kinase for release of prostaglandins