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Neuroscience > neurotransmitter receptor signalling > Flashcards

neurotransmitter receptor signalling Flashcards

1
Q

what are the key fast transmitters in the CNS

A

glutamate glycine GABA

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2
Q

Other fast synaptic transmitters

A

ACh (nAChR) acetylcholine
5HT (5HT3R) serotonin
ATP (P2XRS)

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3
Q

glutamate receptors

A

ionotropic Glu receptors = AMPA, kinate, NMDA
metabotropic Glu receptos = group1, group2, group3

excitatory
90% of synaptic connections in brain

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4
Q

GABA receptors

A

GABA = gama-amino butyric acid

iGABA Rs = GABA(a) and GABA (c)
GABA (b) Rs

inhibitory

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5
Q

Glycine receptors

A

iGlyRs

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6
Q

tetramers of NMDA

A

GluN1-3 subunits

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7
Q

tetramers of AMPA

A

GluA1-4 subunits

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8
Q

tetramers of Kainate

A

GluK1-5 subunits

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9
Q

endogenous agonists of NMDA

A

receptor sites = glutamate aspartate
modulatory site = glycine, D serine

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10
Q

endogenous agonists of AMPA

A

glutamte

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11
Q

endogenous agonists of kainate

A

glutamate

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12
Q

location of NMDA, AMPA and kinate receptor

A

NMDA = postsynaptic, some pre, glial, wide distribution
AMPA = postsynaptic, glial, wide dis
kinate = post and pre, limited distribution

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13
Q

function of NMDA, AMPA and kinase receptor

A

NMDA = slow EPSC, synaptic plasticity (LTP, LTP), excitotoxicity
AMPA = fast EPSC
kainate = fast EPSC, presynaptic inhibition

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14
Q

AMPA receptor subunit topology

A

M1, M3 and M4 transmembrane domains
M2 = rentrant loop = doesn’t go all the way through the membrane

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15
Q

Q/R site on AMPA receptor role

A

determines calcium
permeability of GluA2

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16
Q

why are AMPAs tetramers

A

GluA 1,2,3,4 subunits used in any combination to make functional receptors

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17
Q

glutamate and AMPA

A

glutamate activates AMPA receptors
cause conformational change
sodium ions can move through
fast

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18
Q

glutamate and AMPA

A

glutamate activates AMPA receptors
cause conformational change
sodium ions can move through
fast

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19
Q

properties of AMPA receptors

A
  • 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
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20
Q

AMPA receptors containing GluA2 subunits

A
  • low calcium permeability
  • mRNA editing
  • positively charged arginine residue (R) expressed instead of neutral glutamine (Q) in pore forming M2 region of GluA2
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21
Q

when are AMPA receptor permeable to calcium

A

in the absence of any GluA2 (R) subunits
most have a gluA2R!

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22
Q

kainate receptor subunit topology

A

GluK 1-5 subunits
3 transmembrane domains (M1,M3,M4)
M2 = reentrant loop

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23
Q

Q/R site of kainate receptor

A

determines Ca2+
permeability of GluK1 and K2

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24
Q

what GluK subunits don’t form functional receptors alone

A

GluK4 or GluK5

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25
Q

what do GluK1 and GluK2 undergo at Q/R site

A

undergo RNA editing at pore Q/R site
regulated in development

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26
Q

structure of NMDA receptors

A

Heterotetramer = little bit more structure to subunits = 2x gluN1 and 2x GluN2 subunits

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27
Q

properties of NMDA receptor

A

cation channel
sodium and calcium entry
channel opens = depolarisation

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28
Q

what activates NMDA receptors

A

binding of glutamate (orthosteric site)
co agonist (modulatory site)
e.g glycine or D serine

29
Q

how to NMDA receptors work

A

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

30
Q

coincidence detection

A

can occur when 2 or more inputs coverage on a postsynaptic neurone through rectifying electrical synapses (e.g NMDA)

31
Q

what happens when AMPA and NMDA receptors

A

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)

32
Q

synaptic plasticity

A

ability to change strength of synaptic connections and consolidate new pathways in the CNS

33
Q

long term potentiation

A

long lasting potentiation of synaptic transmission

34
Q

long term depression

A

long lasting of synaptic transmission depression

35
Q

structure of metabotropic Glutamate receptor

A
  • 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
36
Q

properties of metabotropic glutamate receptors

A
  • pre and post synaptic
  • play modulatory role in synaptic transmission
  • control excitability of neurones = modulate signalling through K+ and Ca2+
  • desirable for drug discovery
37
Q

what do postsynaptic group 1 metabotropic glutamate receptor do

A

mediate slow depolarisation

38
Q

what do postsynaptic group 2 and 3 metabotropic glutamate receptors do

A

decrease neurotransmitter release

39
Q

summarise AMPA, NMDA and mGlu receptors

A

AMPA = synaptic transmission
NMDA = coincidence detector
mGluR = modulatory role

40
Q

GABA (a) receptor structure

A
  • anion channel
  • Cl- entry
  • channel opening = hyper polarisation
  • 5 subunits
    = alpha, beta , gamma, delta and p
    most common (a1)2(B2)2(g2)
41
Q

where are GABA(a) receptors found

A

synaptically
short term/phasic inhibition
extrasynaptically - modulating the tone of neural circuits (tonic inhibition, more difficult to fire AP)

42
Q

sedative/hypnotic drugs and GABA(a)

A

sedative/hypnotic drugs enhance GABA a receptor activity via modulatory site

43
Q

what are GABA receptors

A

positive allosteric modulators
activate receptor in different location to orthersteric ligand

44
Q

2 ways GABA produces inhibition

A

By acting both as a fast point to option transmitter and as an action at a distance neruomodulation

45
Q

extra synaptic vs synaptic response

A

Synaptic response = sharp hyperpolarisation of response

Extra-synaptic response = long term inhibitory action = general tonic inhibition = general hyperpolarisation = general slight depolarisation

46
Q

structure of GABA (b) receptors

A

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

47
Q

which is ionoitropic and which is metabotropic - GABA(a) and GABA(b)

A

ionotropic GABA(a)
metabotroptic GABA(b)

48
Q

non specific and specific

7 ways alcohol impacts neural function

A
  1. non specific = alters lipid composition
  2. non specific = interacts with polar heads of phospholipids
  3. non specific = disturpbs the relationship of protein in membrane
  4. specific = acts at neurotrasmitter binding site
  5. specific = modifies gating mechanism inside channel
  6. specific = direct interaction with channel proteins
  7. specific = stimulate Gs which is linked to andenylyl cyclase
49
Q

who can alcohol (ethanol) modulate glutamatergic neurotransmission

A
  • 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
50
Q

how does ethanol dose effect NMDA currents

A
  • 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)
51
Q

does ethanol modulate magnesium block

A
  • ethanol doe not directly modulate the magnesium block
52
Q

why do different regions of the brain recat differently to ethanol

A
  • different glutamate subunits = different ethanol sensitivtiy = why brain regions are impacted differetnly by alcohol
53
Q

how does alcohol inhibit glutamate neurotransmission

A
  • 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
54
Q

how does chronic alchocol intake lead to compensatory adaptations in glutamatergic neurotransmission

A
  • 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
55
Q

behavioral effects of changes in glutamatergic signalling due to alcohol
Acute vs chronic

A

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

56
Q

foetal alcohol syndrome

A

maternal alcohol levels impair glutamatergic isgnalling in the developing brain = reduced NMDA receptors in offspring = development and cognitive impairment

57
Q

acute alcohol effect of GABAergic neurotransmission

A
  • 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
58
Q

what are neurosteroids

A
  • neurosteroids = positive allosteric modulators of GABA(A)
59
Q

how does alcohol increase neurosteroid release in the brain

A

neurosteroids and alcohol have different potencies at different GABA(a) receptor isoforms
alchols = increase neurosteroid release
reduce GABAergic transmission

60
Q

GABA transmission in presences of alcohol Is

A

increased

61
Q

chronic exposure to alcohol effect of GABAergic transmission

A
  • 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
62
Q

Acute and chronic behavioural effects of alcohol mediated by changes in GABAergic signalling

A

acute
- sedative
- anxiety reducing
- impaire coordination
chronic
- alcohol tolerance (change in subunits composition)
- seizures/tremor (hyper excitability due to loss of inhibitory tone)

63
Q

Acute alcohol (ethanol) ………. endogenous opioid synthesis and release

A

increases

64
Q

what are opioids

A

chemicals that act on opioid receptors can be endogenous (made by the body) or exogenous
* endorphins
* enkephalins
* dynorphins
*endomorphins
*nociceptin

65
Q

what are opiates

A

naturally occurring biochemicals that modulate opioid receptors
morphine and heroin

66
Q

how do glial cells modulate synaptic transmission

A

releasing gliotransmitters

impact excitatory transmission
- release glutamate
- release D serine

release neuromodulators
- ATP
- adenosine

67
Q

how does ethanol impact glial cell function

A
  • 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
68
Q

summary of the effects of alcohol

A
  • 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

Neuroscience (14 decks)

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