Receptors Flashcards
where do receptors coordinate communication?
what is this made up of?
what do they all express?
the tripartite synapse
presynaptic terminal
postsynaptic terminal
astrocyte
receptors exclusively involved in coordinating cell signalling events
what is the role of astrocytes and glial cells at the tripartite synapse?
control and fine tune communication events within the synapse
what are the 3 receptor types?
ion channel
GPCR
tyrosine-kinase receptor
what are ionotropic receptors?
what opens them?
what timescale are they in?
give an example
ligand-gated ion channels
the binding of small molecule transmitters or signalling molecules
milliseconds
nicotinic AChR
what is the timescale of metabotropic/GPCRs?
what is their effector?
give 2 examples
seconds
enzyme/channel
muscarinic AChR
adrenoreceptors
what is the timescale of kinase-linked receptors?
what is the effector?
give an example of a signalling molecule that activates this
minutes
enzyme
- Tyrosine-kinase
(phosphorylates targets of tyrosine residues)
insulin
what is the timescale of the steroid/thyroid type receptors?
what is the effector?
give an example of an activating molecule
hours
gene transcription
oestrogen
describe the process of ligand-gated ion channels opening
- ligand binds to ligand binding domain
- changes conformation in receptor structure
- opens pore in membrane
- ions pass through to drive response
describe the process of GPCR signalling
- ligand binds to GPCR
- induces conformational change in G protein
- enables binding of G protein to receptor
- stimulates exchange of GDP for GTP on the protein
- activates the G protein
- dissociation of the alpha beta gamma complex
- normally activity driven by alpha subunit
BUT can be mediated by beta-gamma subunit
-> can control channel opening
describe the process of RTK signalling
- ligand binds to ligand-binding domain
- conformational change in protein
= dimerisation of receptor - activates receptor
- kinase domain has TK activity
- phosphorylation of tyrosine amino acid residues
- residues on the receptor get phosphorylated first
-> activates receptor to signal downstream - involves binding of adaptor proteins (e.g. MAPK) to receptor
many small molecule neurotransmitters can signal through BOTH…?
C-protein coupled receptors
AND
ionotropic ligand-gated ion channels
what are the 3 main effector pathways of GPCR signalling?
norepinephrine
- via Gs
glutamate
- via Gq
dopamine
- via Gi
describe what happens when norepinephrine binds to b-adrenergic GPCR
- induces conformational change in b-adrenergic
- recruitment of Gs
- exchange of GDP and GTP
- activation of G protein -> release of stimulatory alpha subunit
- activates adenylyl cyclase
- produces cAMP
- activates protein kinase A
- increases protein phosphorylation of targets (e.g. ion channels, enzymes, TFs)
describe what happens when glutamate binds to mGluR (GPCR)
- recruits Gq
- activates phospholipase C
- catalyses production of Diacylglycerol and IP3 by hydrolysing PIP2
- Diacylglycerol recruits Protein kinase C
- increases protein phosphorylation
- IP3 binds to IP3 receptors on intracellular calcium stores (e.g. on ER)
- releases Ca2+
- activates calcium-binding proteins
describe what happens when dopamine binds to Dopamine D2 (GPCR)
- recruits Gi (inhibitory)
- inhibits adenyl cyclase activity
- reduces cAMP
- reduction in downstream cAMP signalling events
- decrease in protein phosphorylation
describe ionotropic receptor structure
different permeabilities
multiple subunits
- can be homomeric, BUT normally heteromeric
what are purinoreceptors activated by?
describe their structure
which ions pass through?
ATP
trimeric
= 3 subunits
each subunit has 2 transmembrane domains
Na+
Ca2+
describe the structure of glutamate receptors
which ions pass through?
tetrameric
= 4 subunits
each subunit has 3 transmembrane domains and a re-entrant loop
Na+
Ca2+
what are pentameric receptors activated by?
describe the structure
which ions pass through?
ACh, GABA, Glycine, Serotonin
pentameric
= 5 subunits
each subunit has 4 transmembrane domains
Na+
Ca2+
Cl-
what are the 3 classes of glutamate-gated ionotropic receptors?
what are these sub-divisions based on?
AMPA
NMDA
Kainate
their sensitivity to these synthetic ligands
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?
GluA1-4
GluN1
GluN2a-d
GluN3a-b
GluK1-5
what else do the pentamer receptors have in common?
what is the role of this?
give 2 examples
a Cys-loop in the N-terminus
coupling agonist binding to channel opening
glycine receptors
GABAa receptors
what are the 3 classes of metabotropic glutamate receptors?
what type of system are these involved in?
class I class II class III
second messenger signalling systems
(via GPCR)
what second messengers do the 3 classes of metabotropic glutamate receptors signal through?
class I: excitatory IP3 and Ca2+
class II and III: inhibition of cAMP
what are class II and class III glutamate receptors sometimes referred to as?
why?
autoreceptors
they can be found on the pre-synaptic nerve terminal
- sense glutamate to modulate further NT release
what are the gene families in the metabotropic glutamate families?
class I: mGluR1 + mGluR5
class II: mGluR2 + mGluR3
class III: mGluR4 + mGluR6-8
what do iGluRs work in combination to produce?
describe how AMPA and NDMA receptors are involved in this
excitatory postsynaptic potential (EPSP)
at a glutamatergic synapse:
- glutamate released
- activation of AMPAR
- ion flow across membrane
- rapidly desensitises AMPAR
- depolarisation of membrane
- activates NMDAR
- allows Ca2+ through channel
what does ACh have a predominantly modulatory effect on?
what are the 2 classes of ACh receptor?
brain function
muscarinic
nicotinic
what type of channels are muscarinic and nicotinic receptors?
what are their selective agonists and antagonists?
muscarinic:
GPCR
- agonist = muscarine
- antagonist = atropine
nicotinic:
LGIC
- agonist = nicotine
- antagonist = tubocurarine
what are the subdivisions of muscarinic ACh receptors?
which G protein do they signal via?
M1, M3, M5
via Gq
M2, M4
via Gi
what are the key effectors of M1, M3, M5?
what does this result in?
increased:
phospholipase C
[Ca2+]
MAP kinases
decreased:
M current
increased activity
what are the key effectors of M2 and M4?
what does this result in?
increased:
MAPK
GIRK channels
decreased:
adenylyl cyclase
voltage-gated C2+ channels
decreased activity
describe the structure of nAChRs
how many ACh molecules are required to open the pore?
pentameric LGIC receptors
Cys-loop receptors
5-membrane spanning subunits form a central pore
2 molecules
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?
different subunit combinations producing different nAChR subtypes
homomeric alpha7 nAChRs
heteromeric a4b2 nAChRs
alpha subunits
describe the features of a GABA A receptor
pentameric receptor
cys-loop
4 transmembrane domains
M2 domain lines channel to determine permeability to ions
- normally a Cl- conductance
-> polarises the membrane
= inhibitory
how does the GABA B receptor act?
B1 and B2 subunits heterodimerise
- > couple with Gi
- > releases beta-gamma subunit
- > inhibits adenylyl cylase
= activation of K+ channels or inhibition of Ca2+ channels
what are all dopamine receptors?
what are the 2 sub-types and what are they coupled to?
what are the receptors in these groups?
GPCRs
D1-like (coupled to G-alpha s)
D2-like (coupled to G-alpha i)
D1-like
= D1 + D5
D2-like
= D2, D3 + D4
explain what happens when dopamine receptors heterodimerise
- activate Gq
- activates PLC
- produces IP3
- > Ca2+ release
also produces DAG
-> activates PKC
