neurotransmitter receptor signalling Flashcards
what are the key fast transmitters in the CNS
glutamate glycine GABA
Other fast synaptic transmitters
ACh (nAChR) acetylcholine
5HT (5HT3R) serotonin
ATP (P2XRS)
glutamate receptors
ionotropic Glu receptors = AMPA, kinate, NMDA
metabotropic Glu receptos = group1, group2, group3
excitatory
90% of synaptic connections in brain
GABA receptors
GABA = gama-amino butyric acid
iGABA Rs = GABA(a) and GABA (c)
GABA (b) Rs
inhibitory
Glycine receptors
iGlyRs
tetramers of NMDA
GluN1-3 subunits
tetramers of AMPA
GluA1-4 subunits
tetramers of Kainate
GluK1-5 subunits
endogenous agonists of NMDA
receptor sites = glutamate aspartate
modulatory site = glycine, D serine
endogenous agonists of AMPA
glutamte
endogenous agonists of kainate
glutamate
location of NMDA, AMPA and kinate receptor
NMDA = postsynaptic, some pre, glial, wide distribution
AMPA = postsynaptic, glial, wide dis
kinate = post and pre, limited distribution
function of NMDA, AMPA and kinase receptor
NMDA = slow EPSC, synaptic plasticity (LTP, LTP), excitotoxicity
AMPA = fast EPSC
kainate = fast EPSC, presynaptic inhibition
AMPA receptor subunit topology
M1, M3 and M4 transmembrane domains
M2 = rentrant loop = doesn’t go all the way through the membrane
Q/R site on AMPA receptor role
determines calcium
permeability of GluA2
why are AMPAs tetramers
GluA 1,2,3,4 subunits used in any combination to make functional receptors
glutamate and AMPA
glutamate activates AMPA receptors
cause conformational change
sodium ions can move through
fast
glutamate and AMPA
glutamate activates AMPA receptors
cause conformational change
sodium ions can move through
fast
properties of AMPA receptors
- fast synaptic transmission
- mainly post synaptic localisation
- non selective cation channel
- sodium in
- potassium and calcium out
- ionotropic glutamate receptors - 4 subunits - tetrameric receptor
- AMPA - GluA1,2,3,4
AMPA receptors containing GluA2 subunits
- low calcium permeability
- mRNA editing
- positively charged arginine residue (R) expressed instead of neutral glutamine (Q) in pore forming M2 region of GluA2
when are AMPA receptor permeable to calcium
in the absence of any GluA2 (R) subunits
most have a gluA2R!
kainate receptor subunit topology
GluK 1-5 subunits
3 transmembrane domains (M1,M3,M4)
M2 = reentrant loop
Q/R site of kainate receptor
determines Ca2+
permeability of GluK1 and K2
what GluK subunits don’t form functional receptors alone
GluK4 or GluK5
what do GluK1 and GluK2 undergo at Q/R site
undergo RNA editing at pore Q/R site
regulated in development
structure of NMDA receptors
Heterotetramer = little bit more structure to subunits = 2x gluN1 and 2x GluN2 subunits
properties of NMDA receptor
cation channel
sodium and calcium entry
channel opens = depolarisation
what activates NMDA receptors
binding of glutamate (orthosteric site)
co agonist (modulatory site)
e.g glycine or D serine
how to NMDA receptors work
voltage sensitive magnesium block which is present at physiologic concentrations of magnesium but is removed when cell is depolarised by glycine or glutamate binding to NMDA site
coincidence detection
can occur when 2 or more inputs coverage on a postsynaptic neurone through rectifying electrical synapses (e.g NMDA)
what happens when AMPA and NMDA receptors
activation of AMPA depolarises the membrane sufficiently to remove mg2+ block of NMDA receptors
calcium entry through NMDA is dependent on pre and postsynaptic elements being active at the same time
(NMDA = coincidence detector)
synaptic plasticity
ability to change strength of synaptic connections and consolidate new pathways in the CNS
long term potentiation
long lasting potentiation of synaptic transmission
long term depression
long lasting of synaptic transmission depression
structure of metabotropic Glutamate receptor
- bi lobed N terminal extracellular domain contains glutamate binding site
- cysteine rich domain involved in maintaining tertiary structure
- 7 transmembrane domains (7-TMD) in common with other GPCR families (allosteric modulators bind at sites in the TMD)
- second intracellular loop involved in G protein coupling and determine transduction mechanism
properties of metabotropic glutamate receptors
- pre and post synaptic
- play modulatory role in synaptic transmission
- control excitability of neurones = modulate signalling through K+ and Ca2+
- desirable for drug discovery
what do postsynaptic group 1 metabotropic glutamate receptor do
mediate slow depolarisation
what do postsynaptic group 2 and 3 metabotropic glutamate receptors do
decrease neurotransmitter release
summarise AMPA, NMDA and mGlu receptors
AMPA = synaptic transmission
NMDA = coincidence detector
mGluR = modulatory role
GABA (a) receptor structure
- anion channel
- Cl- entry
- channel opening = hyper polarisation
- 5 subunits
= alpha, beta , gamma, delta and p
most common (a1)2(B2)2(g2)
where are GABA(a) receptors found
synaptically
short term/phasic inhibition
extrasynaptically - modulating the tone of neural circuits (tonic inhibition, more difficult to fire AP)
sedative/hypnotic drugs and GABA(a)
sedative/hypnotic drugs enhance GABA a receptor activity via modulatory site
what are GABA receptors
positive allosteric modulators
activate receptor in different location to orthersteric ligand
2 ways GABA produces inhibition
By acting both as a fast point to option transmitter and as an action at a distance neruomodulation
extra synaptic vs synaptic response
Synaptic response = sharp hyperpolarisation of response
Extra-synaptic response = long term inhibitory action = general tonic inhibition = general hyperpolarisation = general slight depolarisation
structure of GABA (b) receptors
dimer made up of 2 7 transmembrane domains
help together by a coil/coil interaction between their c terminal tails
activation occurs when GABA binds to the extracellular domain of the B1 subunit
located pre and post synaptically
GPCR receptors through Gi/Go
which is ionoitropic and which is metabotropic - GABA(a) and GABA(b)
ionotropic GABA(a)
metabotroptic GABA(b)
non specific and specific
7 ways alcohol impacts neural function
- non specific = alters lipid composition
- non specific = interacts with polar heads of phospholipids
- non specific = disturpbs the relationship of protein in membrane
- specific = acts at neurotrasmitter binding site
- specific = modifies gating mechanism inside channel
- specific = direct interaction with channel proteins
- specific = stimulate Gs which is linked to andenylyl cyclase
who can alcohol (ethanol) modulate glutamatergic neurotransmission
- non competitive antagonist (negative allosteric modulator) = NMDA and AMPA receptors - ionotropic glutmate receptors
- reduced glutamate release from pre synaptic terminal = increases actvitiy of mGLuR2/3 - group 2 metabotropic glutamate receptor
- inhibits excitation = makes you feel drowsy
how does ethanol dose effect NMDA currents
- dependently reversibly inhibits NMDA-induced inward currents in cultured neurones.
- ethanol dose reversibly inhibit NMMDA induced inward currents in cultures neurones (voltage clamp)
- increase ethanol = size of response gets smaller
- non competitve antagonist (negative allosteric modulator)
does ethanol modulate magnesium block
- ethanol doe not directly modulate the magnesium block
why do different regions of the brain recat differently to ethanol
- different glutamate subunits = different ethanol sensitivtiy = why brain regions are impacted differetnly by alcohol
how does alcohol inhibit glutamate neurotransmission
- ethanol inhibits NMDA and AMPA receptors
channels fo not open fully
cation entry into cell is reduced - ethanol may increase activity of mGluR on presynaptic cell = decrease gluatmate release
- reduced activity if the neuron
- fewer nerve signals generated
how does chronic alchocol intake lead to compensatory adaptations in glutamatergic neurotransmission
- increased NMDA and AMPA receptors = post synaptic membrane
- increase ion channel conductance
- reduced glial reuptake of glutamate from synpatic cleft
- desensitisation or downregulation of presynaptic mGlu receptor leading to increased glutamate release
- glutamate levels in cletft = elevated
- more receptors are available = receptors are more active
behavioral effects of changes in glutamatergic signalling due to alcohol
Acute vs chronic
Acute
* amnesia/memory loss = intact NMDA signalling is required for memory formation and long term potentiation
Chronic
* siezures/brain damage/excitotoxicity (withdrawal)
* anxiety disorientation = hyper excitability associated with withdrawal
foetal alcohol syndrome
maternal alcohol levels impair glutamatergic isgnalling in the developing brain = reduced NMDA receptors in offspring = development and cognitive impairment
acute alcohol effect of GABAergic neurotransmission
- positive allosteric modulator (enhances choride influx through GABA (a) receptors)
- enhanced GABA release = acting via pre synpatic (GABA(B) metabotropic receptors)
- exactly how alcohol modulated GABA = unclear
- imacts GABA signalling differently in ventral tegmental area
what are neurosteroids
- neurosteroids = positive allosteric modulators of GABA(A)
how does alcohol increase neurosteroid release in the brain
neurosteroids and alcohol have different potencies at different GABA(a) receptor isoforms
alchols = increase neurosteroid release
reduce GABAergic transmission
GABA transmission in presences of alcohol Is
increased
chronic exposure to alcohol effect of GABAergic transmission
- reduced impact on GABAergic transmission
- change in GABA(A) receptors subunit composition
- reduced sensitivity of GABA(A) receptors to alcohol an neurosteriods
- change in localisation (synaptic vs extra synaptic)
- no change in receptor number
- withdrawal after chronic alcohol use leads to rapid reversion of GABA(A) subunit charges
- contribute to symptoms of withdrawal
Acute and chronic behavioural effects of alcohol mediated by changes in GABAergic signalling
acute
- sedative
- anxiety reducing
- impaire coordination
chronic
- alcohol tolerance (change in subunits composition)
- seizures/tremor (hyper excitability due to loss of inhibitory tone)
Acute alcohol (ethanol) ………. endogenous opioid synthesis and release
increases
what are opioids
chemicals that act on opioid receptors can be endogenous (made by the body) or exogenous
* endorphins
* enkephalins
* dynorphins
*endomorphins
*nociceptin
what are opiates
naturally occurring biochemicals that modulate opioid receptors
morphine and heroin
how do glial cells modulate synaptic transmission
releasing gliotransmitters
impact excitatory transmission
- release glutamate
- release D serine
release neuromodulators
- ATP
- adenosine
how does ethanol impact glial cell function
- astrocyte expression = regionally regulated by dose and time of alcohol exposure
- ethanol increase excitatory amino acid transporter (GLAST and GLT1) expression on astrocytes
- inhibiting GLAST or GLT1 activity reduces reading/ reinforcing properties of alcohol
summary of the effects of alcohol
- modulate neurotransmission
- acute alcohol suppresses glutamatergic and increases GABAergic transmission
- impacts tone of neural circuits = impacting neuromodulators such as opioids
- chronic alcohol use leads to adaptation = neural signalling
- Glial cells modulate synaptic transmission by releasing gliotransmitters and regulating neurotransmitter reuptkae and recycling
