GPCRs Flashcards
(13 cards)
Tripartite Synapse?
Normal synapse surrounded by regulatory astrocytes.
Expression of receptors at nerve terminal and on astrocytes too.
Bidirectional signalling regulates transmission of NTs at synapse.
Glutamine-Glutamate shuttle
ATP released by Astrocytes ats on purinoceptors peritting Na+, Ca2+ entry and K+ efflux - EPSP…
Simple for how RTK’s work?
Important for Neurotrophins and Growth Factors.
Agonist binding triggers receptor dimerisation, stimulating autophosphorylation of tyrosine residues, Phosphorylated residues acts as binding sites for adaptor proteins - signalling in MAP-kinase pathways.
V. important for neural plasticitiy signalling.
What NTs act on only GPCRs?
Dopamine, NA.
5-HT mostly on GPCR - except 5HT3 which is non-selective cation channels for EPSP…
How many subunits for for ionotropic receptors?
ATP is released by astrocytes and acts on excitatory purinergic receptors which are trimeric - Ca2+, Na+ entry and K+ efflux.
Trimeric with 2 TM domains.
Ionotropic Glutamate receptors AMPA, NMDA, and KA are all tetrameric with 3 TM sections, re-entrant loop and have 4 subunits…
=Obligatory heteromeric assemblies..
Pentameric receptors - nACh, GABAa, 5HT3
= 4 TM sections.
Cys loop family particularly.
What is the Cys loop family?
Signature of cys loop superfamily of ionotropic receptors.
N-terminus cys loop may play role in coupling agonist binding to channel opening.
Found often in pentameric receptors like 5HT3, GABAa, nAChR…
Which mGluR’s are excitatory/inhibitory?
mGluR class II and III are GI/Go coupled = mGluR2, 3, 4, 6,7,8…
Class 1 contains mGluR1 and mGluR5 = Gq coupled…
Which dopamine receptors are exctitatory and inhibitory
D2, D3, D4 are all Gi/Go coupled.
D1, D5 are Gs coupled…
D1 found in Substantia nigra…. Caudate/Putamen…
Dopamine are only GPCRs.
What is the structure of GABAa?
GABAa are pentameric assemblies with an extracellular N-terminus Cys loop.
GABA a have 2 alpha. 2 beta and a Gamma subunit.
Regulatory binding sites = drug action of benzodiazepines at interafaces of Alpha/Gamma subunits.
GABA binds at alpha/beta subunits = 2 GABA binding sites/
= Central Cl- channel formed by TM2/
What is the structure of GABAb?
GABA b signals as GPCR.
- open K+ channels so act as IPSP.
Heterodimerisation between GABA b1 and b2 receptors.
GABAb1 has GABA binding site, and GABAb2 has G-protein binding site.
GABAb regulates K+ and Ca2+ channel activity..
IPSP.
nACh receptor structure?
Most are Sodium gated..
Homomeric Alpha7 nACh and heteromeric a4B2 are most abundant in the brain.
With 5 orthosteric sites!!!
nACh are pentameric, with M2 domain lining ion channel.
nAChR also have cys loop at extracellular N terminus.
4 TM domains, with a variable intracellular loop.
What are the most common muscarinic receptors in the brain?
M1 is dominant post-synaptic mAChR located on dendrities = excitatory Gq/11 coupled.
M2 and M4 are inhibitory, Gi/Go coupled.
M3 and M5 are expressed much lower densitiies….
Ionotropic glutamate receptor, iGluR?
KA, NMDA, AMPA.
Are mostly heteromeric, tetramers.
M2 re-entrant loop forms reeptor pore.
NMDA is obligate hetero-tetramer = must have two GluN1.
GluN1 binds glycine.
GluN2/3 binds glutamate.
Intracellular opening of pore has Mg2+ block = Mg2+ block only alleviated by membrane depolarisation.
Glycine and glutamate required to bind for full activity.
AMPA needs to be activated first - to depolarise membrane and remove Mg2+ block from NMDA.
mGluRs?
Constitutive dimers - though heterodimeric assemblies have been proposed, but not yet proven to exist natively.
Class 1 mGluR’s = mGluR1 and mGluR5 = Gq coupled, can interact with scaffolding proteins like Homer - to switch between different effectors/switch coupling.
Contain 2 large extracellular domains called Venus Flytrap Domains (VFDs) which bind glutamate and other orthosteric lignads…
- needs 2 glutamates bound to activate fully.
