Lecture 2 - Receptors

Question 1

What is a receptor?

Answer 1

Protein in nature Cell constituents that bind agonist - high affinity/specificity Conformational change elicits a cellular response

Question 2

What will happen if an antagonist binds to a receptor?

Answer 2

Antagonist won’t cause this conformational change

Question 3

How many supra families of receptors are there?

Answer 3

4

Question 4

What are the supra families of receptors?

Answer 4

Ligand gated ion channel/ionotropic G-protein coupled receptors Kinase linked receptors Nuclear receptors

Question 5

Tim scale of ligand gated ion channels/ ionotropic receptors

Answer 5

Milliseconds

Question 6

Time scale of G-protein couples receptors

Answer 6

Seconds

Question 7

Time scale of kinase linked receptors

Answer 7

Minutes

Question 8

Time scale of nuclear receptors

Answer 8

Hours

Question 9

Examples of ligand-gated ion channels

Answer 9

Nicotinic ACH receptors

Question 10

Examples of G protein coupled receptors/metabotropic receptors

Answer 10

Muscarinic ACH receptors

Question 11

Example of kinase linked receptors

Answer 11

Cytokine receptors

Question 12

Examples or nuclear receptors

Answer 12

Oestrogen receptors

Question 13

Ligand gated ion channels/ ionotropic

Answer 13

Receptors on which fast neurotransmitters act Opening and closing of ion channel lead to hyperpolaridation or depolarisation

Question 14

G-protein coupled receptors

Answer 14

Membrane receptors that are coupled to intracellular effector systems via a G protein Contain receptors for many hormones and slow transmitters Endogenous molecule In binding to the receptor

Question 15

Kinase linked receptors

Answer 15

Large and heterogenous group of membrane receptors responding to protein mediators Comprise extracellular ligand-binding domain linked to intracellular domain by single transmembrane helix Protein phosphorylation and dimerisation of the receptor

Question 16

Nuclear receptors

Answer 16

Do not always start in the nucleus but will migrate toward here where they will have impact on transcription

Question 17

Structure of ligand gated ion channels/ionotropic receptors

Answer 17

4 transmembrane domain 3 cytoplasmic loops 16-20 membrane-spanning segment surrounding a central ion channel

Question 18

Structure of G-protein coupled receptors

Answer 18

7 transmembrane domain Single chain of polypeptide (400-500 residues) Binding domain on outside G protein Coupling domain on the inside

Question 19

Structure of kinase-linked receptor

Answer 19

One membrane spanning domain Binding domain on outside Catalytic domain on the inside

Question 20

Structure of type 4 nuclear receptors

Answer 20

No cell membrane DNA binding domain (region where you find zinc fingers)

Question 21

What is a ligand gated ion prototypical example

Answer 21

nAChR

Question 22

Ligand gated ion channel structure

Answer 22

Pentameric structure ( 5 subunits) 2 ACH Binding sites at the junction of subunits Number of subtypes exist

Question 23

What does ligand gated ion channel bind to?

Answer 23

2 molecules of ACH

Question 24

Major gated Na+ channel, activation results in what?

Answer 24

Change of electrical activity of cell

Question 25

Where are Na+ channel found?

Answer 25

NMJ Autonomic ganglia CNS

Question 26

What was the first characterised GPCR?

Answer 26

Beta-adrenoceptor (1986)

Question 27

What is the typical structure of GPCR?

Answer 27

Typical structure with 7 transmembrane spanning domains

Question 28

Signal transduction

Answer 28

As there are often a number of metabolic steps involved in signal transduction, they are also referred to as metabotropic

Question 29

How many distinct families of GPCR?

Answer 29

3

Question 30

What is family classification of GPCR based on?

Answer 30

Sequence homology

Question 31

Family A of GPCR

Answer 31

Rhodopsin

Question 32

Family B of GPCR

Answer 32

Secretin/glucagon receptor family

Question 33

Family C of GPCR

Answer 33

Metabotrpic Glutamate receptor/ calcium sensor family

Question 34

Which family is most important in terms of numbers?

Answer 34

Rhodopsin

Question 35

Rhodopsin receptors

Answer 35

The largest group. Receptors for most amine neurotransmitters, many neuropeptides, purines, prostaglandin our, cannabinoids

Question 36

Rhodopsin structural features

Answer 36

Short extracellular (N terminal) tail. Ligand binds to transmembrane helices (amine) or to extracellular loops (peptides)

Question 37

secretin/glucagon receptors

Answer 37

Receptors for peptide hormones, including secretin, glucagon, calcitonin

Question 38

Structural features of secretin/glucagon receptor family

Answer 38

Intermediate extracellular tail incorporating ligand-Binding domain

Question 39

Metabotropic Glutamate receptor/ calcium sensor receptors

Answer 39

Small group Metabotropic glutamate receptors, GABA b receptors and Ca2+ sensing receptors

Question 40

Structural features of metabotropic glutamate receptors

Answer 40

Long extracellular tail incorporating ligand-Binding domain

Question 41

What is the potential fourth family of GPCR?

Answer 41

Includes many receptors for pheromones but no pharmacological receptors

Question 42

G proteins are comprised of how many subunits?

Answer 42

3

Question 43

G protein coupling depends on what?

Answer 43

Whether or not an agonist binds

Question 44

In the resting state what does G protein consist of ?

Answer 44

Trimer of alpha, beta and gamma subunits

Question 45

What happens when there is association of trimer with receptors?

Answer 45

Dissociation of GDP from alpha subunit

Question 46

How is G protein activated?

Answer 46

GTP replaces GDP in cleft and causing alpha subunit to dissociate from the beta gamma dimer

Question 47

What is the active form of G protein?

Answer 47

Alpha-GTP

Question 48

What are the G protein targets?

Answer 48

Adenylate cyclase Phospholipase C Ion channels

Question 49

Adenylate cyclase second messenger

Answer 49

Increases generation of CAMP and subsequent protein kinase activation

Question 50

Phospholipase C secondary messenger

Answer 50

Increases generation of DAG and IP3 from PIP2

Question 51

Ion channels secondary messenger

Answer 51

Differentiated from ionotropic receptors by existence of G-protein linkage

Question 52

What are you GPCR susceptible to?

Answer 52

Desensitisation (or tachyphylaxis or down regulation)

Question 53

What are the types of tachyphalaxis ?

Answer 53

Homologous and Heterologous

Question 54

What is homologous tachyphylaxis ?

Answer 54

Effect receptors which the G protein is bound to only

Question 55

What is heterologous tachyphylaxis?

Answer 55

Effects other receptors not only the ones where G protein is bound

Question 56

What characterises kinase linked receptor transduction?

Answer 56

This group of receptors are characterised by the presence of an intercellular tyrosine kinase domain

Question 57

What does kinase linked receptors signal transduction usually involve?

Answer 57

Dimerisation

Question 58

What does dimerisation allow for in kinase linked receptors?

Answer 58

Autophosphorylatin

Question 59

Why are kinase linked receptors important ?

Answer 59

Important in many regulatory processes including action of growth factors and cytokines

Question 60

Nuclear receptor

Answer 60

A receptor family that allows hormone and lipid signals to regulate gene transcription

Question 61

What do nuclear receptors regulate?

Answer 61

Regulate a host of complex phenomena including development, immune function, organ homeostasis and reproduction

Question 62

Why is dimerisation of nuclear receptors important?

Answer 62

DNA binding

Question 63

What does oestrogen do to nuclear receptors?

Answer 63

Oestrogen leads to dimerisation which exposes activation factors

Question 64

Where do Nuclear receptors reside?

Answer 64

In the cytoplasm or the nucleus

Question 65

Class I Nuclear receptors

Answer 65

Tend to be hormonal receptor. Present in cytoplasm Operate as homodimers Mainly endocrine ligands High affinity

Question 66

Class I Nuclear receptors examples

Answer 66

GR, MR, ER, MR

Question 67

Hybrid class nuclear receptors

Answer 67

Mainly endocrine Operate as RXR heterodimers

Question 68

Hybrid class nuclear receptors examples

Answer 68

TR and VDR

Question 69

Class II Nuclear receptors

Answer 69

Retinoid transporters Present in the nucleus Operate as Heterodimers (except RXR) Mainly lipid ligands Low affinity

Question 70

Class II nuclear receptors examples

Answer 70

PPAR, LXR, FXR, RXR

Question 71

Examples of non receptor drug targets

Answer 71

Voltage gated channels Transporters Enzymes