Neurotransmitter receptor signalling

what is a neurotransmitter?

a chemical substance which is released at the end of a nerve fibre by the arrival of a nerve impulse and, by diffusing across the synapse, effects the transfer of the impulse to another nerve fibre, muscle fibre, ect

what is a neuromodulator?

something that alters the strength and response of a neuron to a neurotransmitter

name 6 chemical mediators in the CNS:

1. 'traditional' small molecule transmitters (ie GABA, ACh, ect)

2. neuropeptides

3. lipid mediators

4. nitric oxide

5. neurotrophins & cytokines

6. steroids

what chemical mediators in the CNS have the main functional role of neuromodulation?

1. small molecule transmitters

2. neuropeptides

3. lipid modulators

4. nitric oxide

what is the main functional role of steroids?

functional plasticity

what is the main functional role of neurotrophins and cytokines?

neuronal growth, survival and functional plasticity

what is the role of 'traditional' small molecule transmitters, like GABA, glutamate, ACh, ect?

fast and slow synaptic transmission, and neuromodulation

usually how many types of neurotransmitters may 1 neuron release?

1

what are the two types of small molecule neurotransmitters?

amino acids and biogenic amines

what are the 4 small molecule neurotransmitters of the amino acid subtype?

Glutamate, Aspartate, GABA, and Glycine

what small molecule neurotransmitters that are amino acids, are excitatory?

Glutamate and Aspartate

what small molecule neurotransmitters that are amino acids, are inhibitory?

GABA

what small molecule neurotransmitters that are amino acids, are both inhibitory and excitatory?

Glycine

what 3 neurotransmitters make up small molecule neurotransmitters that are Biogenic amines?

ACh, Histamine, and monoamines

what are the monoamines that found in the small molecule neurotransmitters biogenic amine group?

Serotonin(5-HT) and catecholamines

what are the catecholamines?

noradrenaline, adrenaline, and dopamine

what determines if the biogenic amines are excitatory or inhibitory?

the downstream receptors activated

what excitatory, fast neurotransmitter accounts for >90% of synaptic connections in the human brain?

Glutamate

what are the 2 types of glutamate receptors?

ionotropic and metabotropic

what are the 3 subtypes of ionotropic glutamate receptors?

NMDA, AMPA, and Kainate

what subtype of ionotropic glutamate receptor, makes up the vast majority of fast synaptic transmission?

AMPA

what is the endogenous and otherwise agonists of AMPA receptors?

endogenous: Glutamate other: AMPA

where can you find AMPA receptors?

postsynaptic with wide distribution throughout CNS

what is the endogenous and otherwise agonists of Kainate receptors?

endogenous: Glutamate other: Kainate

where can you find Kainate receptors?

have a limited distribution throughout the CNS, found both presynaptic and postsynaptic

what is the function of kainate receptors?

fast ESPC/synaptic transmission and presynaptic transmission

What is different about the activation of NMDA receptors?

it requires modulators as well as an agonist/ligand to be activated

what is the endogenous agonists and modulators of NMDA receptors?

endogenous: for the receptor site: both Glutamate, and Aspartate for the modulatory site: Glycine, and D-serine other agonists: NMDA other modulators: polyamines

where can you find NMDA receptors?

widely distributed across CNS- mostly postsynaptic, some presynaptic

what is the function of NMDA receptors?

• Slow EPSP
• Synaptic plasticity (LTP, LTD)
• Excitotoxicity

What does EPSC stand for?

excitatory postsynaptic current

how can you block synaptic transmission of a glutamatergic neuron?

by blocking the post-synaptic cells AMPA receptors with a selective AMPA receptor antagonist (like NBQX)

what do ionotropic glutamate receptors subunits comprise together to form?

a tetrameric receptor

what are the 4 different AMPA receptor subunits in mammals that are 'mixed and matched'?

GluA1, GluA2, GluA3, and GluA4

what AMPA subunit has the lowest Ca2+ permeability?

GluA2

when are AMPA receptors permeable to Ca2+?

When GluA2 is absent (which is rare)

what of the 3 glutamatergic receptors does Kainate most resemble?

AMPA

what is the main difference between AMPA and NMDA receptors?

Ca2+ can easily flow into NMDA receptors

what is required for NMDA receptors to activate?

binding of glutamate at the orthosteric site and a co-agonist at the modulators site

what block does NMDA receptors have on what ion, and describe how it behaves?

NMDA has a voltage-sensitive Mg2+ block which is present at physiologic concentrations of Mg2+ however disappears when depolarized

what 2 glutamatergic receptors usually occur at the same synapse?

AMPA and NMDA

at a synapse with AMPA and NMDA present, describe the process necessary for Ca2+ entry into NMDA receptors:

activation of AMPA receptor at same synapse results in NMDA depolarisation- removing Mg2+ block. Thus Ca2+ entry through NMDA is enabled

what are the first 2 steps of G-protein coupled receptor activation?

1. Ligand binding induces GDP to GTP exchange on the Ga subunit
2. this causing the Ga subunit to dissociate from the By complex

what are the last 2 steps of G-protein coupled receptor activation?

3. Ga subunit, and By complex then activate their downstream targets
4. when bound to the target GTPase activity of Ga subunit is increased leading to hydrolysis of GTP to GDP

what are the 3 main g-protein subtypes?

1. Gas
2. Gai/o
3. Gaq

what is the main function of Gas (GPCR)?

stimulates adenylyl cyclase, causing increased cAMP formation

is Gas GPCRs excitatory or inhibitory?

excitatory

what is the main function of Gai/o (GPCR)?

inhibiting adenylyl cyclase, causing decreased cAMP formation

is Gai/o GPCRs excitatory or inhibitory?

inhibitory

what is the main function of Gaq (GPCR)?

activated phospholipase C, increasing production of second messengers

is Gaq GPCRs excitatory or inhibitory?

excitatory

what are the 3 broad subtypes of metabotropic glutamate receptors?

Group1: mGlu1 & mGlu5 Group2: mGlu2 & mGlu3 Group3: mGlu4, mGlu6-8

what G-protein is coupled onto each group of the metabotropic glutamate receptors?

group1: Gaq group2: Gai/o group3: Gai/o

where is group 1 metabotropic glutamate receptors found?

postsynaptic

where is group 2 & 3 metabotropic glutamate receptors found?

presynaptic

what is the function of group 1 metabotropic glutamate receptors?

slow excitatory transmission, and they increase intracellular calcium and modify ionotropic glutamate receptors responses

what is the function of group 2 & 3 metabotropic glutamate receptors?

slow inhibitory transmission (reduce neuronal excitability), and can be auto-receptors (by reducing glutamate release) OR hetero-receptors (modulating GABA release)

what is the 4 key structures of mGlu receptors?

1. Bi-lobed N-terminal extracellular domain containing glutamate binding site
2. cysteine rich domain involved in maintaining 3' structure
3. 7 transmembrane domains
4. 2nd intracellular loop involved in G-protein coupling and in determining transduction mechanisms

what are the 3 properties of metabotropic glutamate receptors?

1. generally playing a modulatory role in synaptic transmission
2. postsynaptic group 1 mGlu receptors mediate slow depolarisation
3. presynaptic group 2 & 3 mGlu receptors decrease neurotransmitter release
4. modulate signalling- controlling the excitability of neurons

what do metabotropic Glutamate receptors use to modulate neuronal signalling?

K+ and Ca2+

what is the CNS's main inhibitory neurotransmitter?

GABA

what type of drug enhances GABAa receptor activity, and via what?

sedative/hypnotic drugs via the modulatory site

how many subunits make up a GABAa receptor?

5

what do the subunits of GABAa receptors form? and what is it selective to?

a pore/ anion channel, selective to Cl-

what happens when GABA binds to one of the GABAa binding sites?

Cl- pass through the membrane channels, the membrane potential hyperpolarises- leading to an Inhibitory PostSynaptic Potential

what type of receptors are GABAb & GABAa receptors?

B: metabotropic/ g-protein coupled receptors A: ionotropic

how many transmembrane subunits do GABAb receptors have? How are they held together?

7, held together by a coil/coil interaction between their C-terminal tails

when does activation occur for GABAb receptors?

when GABA binds to the B1 subunit

where are GABAb receptors located?

pre and post synaptically

name the 3 non-specific ways alcohol effects neurotransmission?

1. alters lipid composition (disrupt it)
2. interacts with polar heads of phospholipids (disrupt it)
3. disturbs the relationship of protein in the membrane (i.e leaky)

name the 4 specific ways alcohol effects neurotransmission?

1. binds to neurotransmitter binding sites
2. modifies gating mechanisms inside channels
3. directs interactions with channel proteins
4. stimulates g-protein signalling, Gs in particular which is linked to adenylyl cyclase

what are the two ways Alcohol modulates glutamatergic neurotransmission?

1. non-competitive antagonism (binding to NMDA & AMPA receptors and stops them working, without preventing agonist binding)
2. reduced glutamate release from pre-synaptic terminal (by increasing group 2 metabotropic glutamate receptor/mGlueR2/3 activity)

why are different brain regions impacted differently by alcohol?

different glutamate receptor subunits have different ethanol sensitivity

how does alcohol acutely inhibit glutamate neurotransmission?

decreases release of glutamate: ethanol may Inc. activity of mGluR on presynaptic cell= decrease of glutamate released. inhibits NMDARs & AMPARs (which glu activates): channels don't open fully, leading to reduced cation entry into cell this results in less post-synaptic activity, so fewer APs:

what does chronic alcohol consumption result in (glutamatergically)?

compensatory adaptations to glutamatergic neurotransmission: presynaptic neuron: inc. glutamate released glial cells/astrocytes: reduced uptake of glutamate cleft: glutamate levels are elevated post synaptic neuron: more receptors are available, receptors more active this results in excessive activity of the neuron (and can lead to things like seizures)

why does acute alcohol consumption lead to memory loss? (casual drinking)(glutamatergically)

intact NMDA signalling (which alcohol inhibits) is required for memory formation, LTP

what symptoms does chronic/withdrawal alcohol consumption cause (glutamatergically)?

seizures/brain damage/ excitotoxicity during withdrawal, due to excess activity also anxiety and disorientation as withdrawal is associated with hyper-excitability

how does Foetal alcohol syndrome effect the baby's neurotransmission (glutamatergically)?

maternal alcohol levels impair glutamatergic signalling in the developing brain= reduced NMDA receptors in offspring. this can result in developmental & cognitive impairment

what are the 2 ways alcohol modulates GABAergic neurotransmission?

1. positive allosteric modulation (makes channel work better): enhances Cl- influx through GABAa receptors
2. enhanced GABA release: acting on pre-synaptic GABAb receptors

what effect does chronic exposure to alcohol have on GABAergic transmission?

reduces the impact of GABAergic transmission by changing the properties of the GABA receptors, reducing the sensitivity of GABAa receptors to alcohol and/or neurosteroids, and changing the localisation. it is not thought to change the no. of receptors

what GABA receptor has an ethanol binding site?

GABAa

what are the behavioural effects of acute alcohol consumption mediated by changes in GABAergic signalling?

reduces GABAergic signalling resulting in: sedative effects, anxiety-reducing, impaired co-ordination

what are the behavioural effects of chronic/withdrawal alcohol consumption mediated by changes in GABAergic signalling?

enhances GABAergic signalling resulting in: alcohol tolerance by changing subunit composition, and seizures and tremors (cased by hyper-excitability due to loss of inhibitory tone)