Receptors

Question 1

where do receptors coordinate communication?

what is this made up of?

what do they all express?

Answer 1

the tripartite synapse

presynaptic terminal
postsynaptic terminal
astrocyte

receptors exclusively involved in coordinating cell signalling events

Question 2

what is the role of astrocytes and glial cells at the tripartite synapse?

Answer 2

control and fine tune communication events within the synapse

Question 3

what are the 3 receptor types?

Answer 3

ion channel
GPCR
tyrosine-kinase receptor

Question 4

what are ionotropic receptors?

what opens them?

what timescale are they in?

give an example

Answer 4

ligand-gated ion channels

the binding of small molecule transmitters or signalling molecules

milliseconds

nicotinic AChR

Question 5

what is the timescale of metabotropic/GPCRs?

what is their effector?

give 2 examples

Answer 5

seconds

enzyme/channel

muscarinic AChR
adrenoreceptors

Question 6

what is the timescale of kinase-linked receptors?

what is the effector?

give an example of a signalling molecule that activates this

Answer 6

minutes

enzyme
- Tyrosine-kinase
(phosphorylates targets of tyrosine residues)

insulin

Question 7

what is the timescale of the steroid/thyroid type receptors?

what is the effector?

give an example of an activating molecule

Answer 7

hours

gene transcription

oestrogen

Question 8

describe the process of ligand-gated ion channels opening

Answer 8

1. ligand binds to ligand binding domain
2. changes conformation in receptor structure
3. opens pore in membrane
4. ions pass through to drive response

Question 9

describe the process of GPCR signalling

Answer 9

1. ligand binds to GPCR
2. induces conformational change in G protein
3. enables binding of G protein to receptor
4. stimulates exchange of GDP for GTP on the protein
5. activates the G protein
6. dissociation of the alpha beta gamma complex
7. normally activity driven by alpha subunit

BUT can be mediated by beta-gamma subunit
-> can control channel opening

Question 10

describe the process of RTK signalling

Answer 10

1. ligand binds to ligand-binding domain
2. conformational change in protein
   = dimerisation of receptor
3. activates receptor
4. kinase domain has TK activity
5. phosphorylation of tyrosine amino acid residues
6. residues on the receptor get phosphorylated first
   -> activates receptor to signal downstream
7. involves binding of adaptor proteins (e.g. MAPK) to receptor

Question 11

many small molecule neurotransmitters can signal through BOTH…?

Answer 11

C-protein coupled receptors
AND
ionotropic ligand-gated ion channels

Question 12

what are the 3 main effector pathways of GPCR signalling?

Answer 12

norepinephrine
- via Gs

glutamate
- via Gq

dopamine
- via Gi

Question 13

describe what happens when norepinephrine binds to b-adrenergic GPCR

Answer 13

1. induces conformational change in b-adrenergic
2. recruitment of Gs
3. exchange of GDP and GTP
4. activation of G protein -> release of stimulatory alpha subunit
5. activates adenylyl cyclase
6. produces cAMP
7. activates protein kinase A
8. increases protein phosphorylation of targets (e.g. ion channels, enzymes, TFs)

Question 14

describe what happens when glutamate binds to mGluR (GPCR)

Answer 14

1. recruits Gq
2. activates phospholipase C
3. catalyses production of Diacylglycerol and IP3 by hydrolysing PIP2
4. Diacylglycerol recruits Protein kinase C
5. increases protein phosphorylation
6. IP3 binds to IP3 receptors on intracellular calcium stores (e.g. on ER)
7. releases Ca2+
8. activates calcium-binding proteins

Question 15

describe what happens when dopamine binds to Dopamine D2 (GPCR)

Answer 15

1. recruits Gi (inhibitory)
2. inhibits adenyl cyclase activity
3. reduces cAMP
4. reduction in downstream cAMP signalling events
5. decrease in protein phosphorylation

Question 16

describe ionotropic receptor structure

Answer 16

different permeabilities

multiple subunits
- can be homomeric, BUT normally heteromeric

Question 17

what are purinoreceptors activated by?

describe their structure

which ions pass through?

Answer 17

ATP

trimeric
= 3 subunits

each subunit has 2 transmembrane domains

Na+
Ca2+

Question 18

describe the structure of glutamate receptors

which ions pass through?

Answer 18

tetrameric
= 4 subunits

each subunit has 3 transmembrane domains and a re-entrant loop

Na+
Ca2+

Question 19

what are pentameric receptors activated by?

describe the structure

which ions pass through?

Answer 19

ACh, GABA, Glycine, Serotonin

pentameric
= 5 subunits

each subunit has 4 transmembrane domains

Na+
Ca2+
Cl-

Question 20

what are the 3 classes of glutamate-gated ionotropic receptors?

what are these sub-divisions based on?

Answer 20

AMPA
NMDA
Kainate

their sensitivity to these synthetic ligands

Question 21

what are the 4 subunits of AMPA receptors?

what about the 7 subunits of NMDA receptors?

what are the 5 subunits of the kainate receptors?

Answer 21

GluA1-4

GluN1
GluN2a-d
GluN3a-b

GluK1-5

Question 22

what else do the pentamer receptors have in common?

what is the role of this?

give 2 examples

Answer 22

a Cys-loop in the N-terminus

coupling agonist binding to channel opening

glycine receptors
GABAa receptors

Question 23

what are the 3 classes of metabotropic glutamate receptors?

what type of system are these involved in?

Answer 23

class I 
class II
class III

second messenger signalling systems
(via GPCR)

Question 24

what second messengers do the 3 classes of metabotropic glutamate receptors signal through?

Answer 24

class I:
excitatory IP3 and Ca2+

class II and III:
inhibition of cAMP

Question 25

what are class II and class III glutamate receptors sometimes referred to as? why?

Answer 25

autoreceptors they can be found on the pre-synaptic nerve terminal - sense glutamate to modulate further NT release

Question 26

what are the gene families in the metabotropic glutamate families?

Answer 26

``` class I: mGluR1 + mGluR5 ``` ``` class II: mGluR2 + mGluR3 ``` ``` class III: mGluR4 + mGluR6-8 ```

Question 27

what do iGluRs work in combination to produce? describe how AMPA and NDMA receptors are involved in this

Answer 27

excitatory postsynaptic potential (EPSP) at a glutamatergic synapse: 1. glutamate released 2. activation of AMPAR 3. ion flow across membrane 4. rapidly desensitises AMPAR 5. depolarisation of membrane 6. activates NMDAR 7. allows Ca2+ through channel

Question 28

what does ACh have a predominantly modulatory effect on? what are the 2 classes of ACh receptor?

Answer 28

brain function muscarinic nicotinic

Question 29

what type of channels are muscarinic and nicotinic receptors? what are their selective agonists and antagonists?

Answer 29

muscarinic: GPCR - agonist = muscarine - antagonist = atropine nicotinic: LGIC - agonist = nicotine - antagonist = tubocurarine

Question 30

what are the subdivisions of muscarinic ACh receptors? which G protein do they signal via?

Answer 30

M1, M3, M5 via Gq M2, M4 via Gi

Question 31

what are the key effectors of M1, M3, M5? what does this result in?

Answer 31

increased: phospholipase C [Ca2+] MAP kinases decreased: M current increased activity

Question 32

what are the key effectors of M2 and M4? what does this result in?

Answer 32

increased: MAPK GIRK channels decreased: adenylyl cyclase voltage-gated C2+ channels decreased activity

Question 33

describe the structure of nAChRs how many ACh molecules are required to open the pore?

Answer 33

pentameric LGIC receptors Cys-loop receptors 5-membrane spanning subunits form a central pore 2 molecules

Question 34

what do the multiple genes coding for nAChR subunits enable? what is the most abundant nAChRs in the brain? which subunits dictate the ACh binding sites?

Answer 34

different subunit combinations producing different nAChR subtypes homomeric alpha7 nAChRs heteromeric a4b2 nAChRs alpha subunits

Question 35

describe the features of a GABA A receptor

Answer 35

pentameric receptor cys-loop 4 transmembrane domains M2 domain lines channel to determine permeability to ions - normally a Cl- conductance -> polarises the membrane = inhibitory

Question 36

how does the GABA B receptor act?

Answer 36

B1 and B2 subunits heterodimerise - > couple with Gi - > releases beta-gamma subunit - > inhibits adenylyl cylase = activation of K+ channels or inhibition of Ca2+ channels

Question 37

what are all dopamine receptors? what are the 2 sub-types and what are they coupled to? what are the receptors in these groups?

Answer 37

GPCRs D1-like (coupled to G-alpha s) D2-like (coupled to G-alpha i) D1-like = D1 + D5 D2-like = D2, D3 + D4

Question 38

explain what happens when dopamine receptors heterodimerise

Answer 38

1. activate Gq 2. activates PLC 3. produces IP3 - > Ca2+ release also produces DAG -> activates PKC