Y1S2W8 - Receptors

Question 1

State 4 objectives/challenges in communication of information?

Answer 1

1. Causing the desired effect
2. Timeliness - speed/time of delievry
3. Imparting the correct information
4. Reaching the right target/recipient

Question 2

What type of molecule is a receptor?

Answer 2

Protein

Question 3

examples of naturally occuring receptors?

Answer 3

Hormones, neurotransmitters and local chemical mediators (e.g. histamine)

Question 4

Summary of Signal Transduction?

Answer 4

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.

Question 5

Purpose of extra-cellular recipients? What is the need?

Answer 5

Water soluble/polar and endogenous signalling molecules cannot diffuse across membranes (fatty/non-polar) - they bind to receptor proteins on the SURFACE

Question 6

Intracellular proteins?

Answer 6

Hydrophobic drugs can cross membrane and bind to receptors within the cell to have effect.

Question 7

Two classifications of receptor proteins?

Answer 7

1. Pharmacological Classification - nature of drug/ligand

2. Signal Transduction Pathway/Structural Classification - 3D structure

Question 8

What is a G-Protein Linked/Coupled Receptor? (GPCR’S)

Answer 8

Largest, most diverse group of membrane
surface receptors

G protein is not a receptor, protein joins with a receptor to ‘work’

Question 9

Where are GPCR’s involved?

Answer 9

vision, smell, behaviour, mood, immune system, inflammation, autonomic nervous system

Question 10

Structure of G-protein linked/coupled receptor?

Answer 10

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

Question 11

How G-Proteins work/Signal Transduction Pathway

Answer 11

1. Chemical messenger binds to receptor leading to complete change of shape
2. This opens binding site so G-protein can interact
3. Once bound, g-protein subunits fragments
4. subunit travels through membrane and binds to allosteric site of enzyme
5. Enzyme alters shape and opens active site which causes reaction

Question 12

Relevance to pharmacy?

use?

Answer 12

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

Question 13

What are the GPCR subunits?

Answer 13

alpha, beta and gamma

Question 14

Which molecules are bound to G protein? Importance?

Answer 14

GDP and GTP - guanyl di/tri-phosphate

When phosphate is added/removed something is happening/stopping

Question 15

Roles of GDP/GTP

Answer 15

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

Question 16

What happens after trasnduction pathway?

Answer 16

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

Question 17

How is the signal stopped?

Answer 17

Alpha subunit has intrinsic GTPase which breaks down phosphate, converting GTP-GDP

Subunits reform the G-protein and stops the signal tranmitting

Question 18

How is the signal stopped?

Answer 18

Alpha subunit has intrinsic GTPase which breaks down phosphate, converting GTP-GDP

Subunits reform the G-protein and stops the signal transmitting

Question 19

What are agonists/antagonists?

Answer 19

agonist - encourages

antagonist - inhibits

Question 20

What is a ligand gated ion channel?

Answer 20

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

Question 21

Receptor structure in ion channels

Answer 21

• 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)

Question 22

Ion channel link to pharmacy

Answer 22

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

Question 23

Drug classes that alter ion channels

Answer 23

1. Local anaesthetic

2. Benzodiazepines

Question 24

Tyrosine Kinase Receptor?

Answer 24

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

Question 25

Structure of TKR?

Answer 25

Transmembrane unit

Single extracellular region (N-terminal) - site for messenger

Single intracellular region - enzyme (C-terminal)

Question 26

How does TKR work?

Answer 26

Resting/active state

Rests until ligand binds, changing shape to reveal active site on C-Terminus (phosphorylation of tyrosine residues can occur)

Question 27

Example of TK receptor (target for cancer drug)

Answer 27

Receptor for Epidermal Growth Factor (EGF)

EGF is bivalent - can bind to 2 receptors at once: very efficient

Question 28

How do intracellular receptors work?

Answer 28

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

Question 29

Intracellular receptor structure?

Answer 29

Non-membrane bound

Single protein containing ligand binding site and DNA binding site

DNA binding site/Zinc fingers = able to identify specific nucleotide sequence

Question 30

Famous example of intra-receptor and drug

Answer 30

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