Molecular Pharmacology - Synaptic Receptors Flashcards by ahmad elmowag

what are the features of dendrites

input - afferent
short and multiple processes
markers - MAP2
postsynaptic spines

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what are the features of axons

output - efferent
thinner and longer than dendrites
markers - Tau
postsynaptic terminals

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function of basket cells

they target alpha-1 receptors
regulate the generation of action potentials from pyramidal neurones in layer 5

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what is an experimental method to study heterologous receptors using HEK cells

transfect the HEK cells with plasmids carrying the sequence of interest and a fluorescent marker (GFP)
wait ~3 days for expression and membrane insertion of protein channels

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what is an experimental method used to study heterologous receptors using oocytes

microtransplantation:
take human tissue - extract the mRNA of interest
inject said mRNA into xenopus oocyte
wait for expression to study receptor of interest

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outline the brain slice technique

brain is rapidly extracted and sliced in ice-cold cerebrospinal fluid
slices survive for up to 12 hours

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what are the pros of the brain slice technique

network connectivity is preserved
anatomically identifiable regions
allows for single cell recording and identification of cells

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what glutamate receptors are responsible for fast excitation

AMPA
Kainate

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what glutamate receptor is responsible for coincidence detection

NMDA

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what are iGluR

selective cationic channels

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what is the reversal potential for cationic channels in neurones

0mV

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what happens when cationic channels in neurones open

the cell depolarises - brings the cell closer to threshold
- generates excitatory effect

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what is permeability of all ion channels dictated by

the ion channel molecule

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what is decay time

how long does the receptor hold onto the neurotransmitter

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what is the decay time for AMPA and NMDA

AMPA - 3ms
NMDA - 40-2000ms

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where is the C-terminus of GABA receptors located (AMPA/NMDA)

located intracellularly
important for scaffolding and function

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what is the overall structure of glutamate receptors

3 transmembrane domains
1 reentrant loop
intracellular C-terminus
extracellular N-terminus
ligand binding domain is made from N-terminus region S1 and S2

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what is required for AMPAR activation

binding of one glutamate to subunit to open the AMPA pore
conductance (g=I/V) is agonist dependent

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what is required for NMDAR activation

2 molecules of glutamate must bind to GluN2 subunits
2 molecules of glycine - co-agonist - must bind to GluN1 subunits, D-serine can also serve this function
conductance of NMDAR is agonist independent

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what does conductance mean

if something’s conductance is agonist dependent then the amount of agonist influences the degree to which the receptor/pore is activated/opened and vice versa for independent

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outline the conductance of AMPA

so there are 4 subunits to AMPA, each with a glutamate binding site
if one glutamate is bound then 1 quarter of the pore is open, the more glutamate bound to each unit the more the pore opens

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what is the S1 and S2 regions connected by

a glycine-threonine linker

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why are NMDAR voltage dependent

because of Mg2+ blockade

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what do NMDAR act as

coincidence detectors after repetitive stimulation
permeate Ca2+ into the neurone - activates many secondary messengers

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what is present on the GLUA2 sequence that codes for one of the glutamate receptor domains

codes for the reentrant loop Q/R is present in the sequence present in the pore lining dictates permeability of the pore

what is the feature of GLUA2 lacking AMPAR

is Ca2+ permeable inwardly rectifying conductance high-single channel conductance fast deactivation time

what are TARPs

Transmembrane AMPAR Regulatory Proteins different subtypes: gamma1-gamma8 y2 is known as stargazin they effect trafficking and function

what is necessary for the super-activation of glutamate receptors

the concerted action of L1 and L2 extracellular loops on TARPs

what is the obligatory subunit of NMDA receptors for their expression

GluN1

during development, which NMDA subunit is most prominent

GluN2B

when does GluN2A expression increase

in adults

what does Glun2B contain

a PDZ binding domain

what is the function of a PDZ binding domain

binds to PSD-95 and promotes synaptic localisation

for GABA receptors in maturing and adult physiology, what is the mM of Cl- inside and outside cell

outside - both 110mM inside maturing - 30mM inside adult - 5mM

for GABA receptors in maturing and adult physiology, what voltage does the membrane want to rest at and why

adult = -82mV maturing = - 34mV caused by the distribution of Cl-

what leads to the difference in internal Cl- mM from maturing to adult

KCC2 becomes more efficient at exporting Cl- to outside the cell as the physiology matures

what are the features of GABA receptors

fast inhibition tonic inhibition

how many transmembrane domains do metabotropic receptors have

what type of receptors are metabotropic receptors

Class C GPCR

what is each subunit of metabotropic receptors made from

made from an extracellular venus fly trap domain (VFTD) that binds agonists and links to the 7 transmembrane domains

what are mGlu receptors

homodimeric receptors - 2 metabotropic receptors

what is required to form i dimer for mGlu formation

intramolecular disulfide bridges in both VFTDs

what is required for mGluR activation

efficient signalling - glutamate binds to both VFTDs can also activate from just one glutamate to one VFTD but less efficient

which mGlu5R subtypes are more predominant during postnatal period and adulthodd

mGluR5a - postnatal period mGluR5b - adulthood

what is mGluR5

a group 1 receptor - mostly postsynaptic can form homo/heterodimers

what is the function of mGluR5

regulates mechanisms in neurogenesis and synaptic regulation

what can disregulation of mGluR5 cause

Fragile X syndrome autism schizophrenia Alzheimer's

what do distinct binding pockets of for NAMs in Glu1 and Glu5 reveal

that multiple sites in class C 7TMDs can bind allosteric regulators

what can mGlu5 antagonists do

restore amyloid-beta inhibited LTP to normal levels

what is the pathology of fragile X syndrom

mGlu5R activation is way too much leads to way to much translation machinery being activated - transcribes mRNA into too many proteins that cause too much endocytosis of AMPA receptors - too few AMPA receptors are expressed on the surface

what is the function of FMRP

inhibits translation machinery from transcribing mRNA - pivotal for preventing Fragile X syndrome

what can GABAb receptors modulate

modulates the firing rate of basal ganglia neurons in the brain

what is the structure of a GABAb receptor

GABAb1a - contains 2 N-terminal sushi domains (SD) - axonal localisation GABAb1b - dendritic localisation

what are the functions of the GABAb subunits

GABAb1a - contains the VFTD agonist binding site GABAb1b - couples to the G-protein

what are the functions of dopamine releasing neurones in the basal ganglia

steady, autonomous pacemaking self-generated mechanism maintains extracellular dopamine levels

how does GABA what can GABAb receptors form

supercomplexes - when heterodimers self-assemble into tetramers or oligomers

how are supercomplexes formed

via interactions of the VFTD on GABAb1a

what would happen if you applied a GABAb antagonist to dopamine releasing neurones in the basal ganglia

they inhibit it the graph of activity goes silent

what does GABAb lack

lacks a cysteine-rich domain - its more compact

in terms of activation what is the difference between GABAb and mGlu heterodimers

GABAb only requires one agonist per dimer for full activation

what are KCTDs

K+ channel tetramarisation domains are GABAb receptor components that act as auxillary receptor subunits they are not K+ channels they help GABAb link with other proteins

what are the core building blocks of GABAbR

GABAb1a GABAb1b KCTD G-protein

Molecular Pharmacology - Synaptic Receptors Flashcards

(63 cards)