GPCRs Flashcards
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.
