Neurotransmitters/receptors

What is a neurotransmitter?

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

• usually a neuron will only submit one type of NT e.g. glutamatergic…

Effects on neurotransmission

Excitatory → increases likelihood of generating and action potential in the post-synaptic neuron

Inhibitory → decreases the likelihood

Neuromodulators

→ substance or device that alters nerve activity by affecting synaptic transmission

• unlike NTs, neuromodulators don’t directly transmit signals across a synapse, but influence the strength and response of neurons

• E.g. hormones, amino acids

Traditional ‘small’ molecule NTs

Chemical mediators in the CNS

1. Traditional ‘small’ molecule NTs = fast/slow synaptic transmission, neuromodulation too

2. Neuroleptics = neuromodulators

3. Lipid mediators = neuromodulators

4. Nitric oxide = neuromodulators

5. Neurotrophins, cytokines = neuronal growth/survival

6. Steroids = functional plasticity

Glutamate

• main excitatory NT in the brain

• >90% of synaptic connections in the brain

• Ionotropic receptors = iGluRs (AMPA, NMDA, Kainate)

• Metabotropic receptors = mGluRs (grp 1, grp 2…)

• Fast NT

GABA

Gamma-amino butyric acid

• main inhibitory NT in the CNS

• Fast NT

• Ionotropic receptors = iGABARs (GABAa, GABAc)

• Metabotropic receptors = GABAb receptors

Ionotropic Glutamate receptors

AMPA, NMDA, Kainate

AMPA receptors

Properties:

• mediate majority of fast excitatory transmission

• Non-selective cation (+ve) channels permeable to Na+ (in) and K+ (out)

• 4 subunits to form a tetrameric receptor

• GluA1-4, which mix and match to produce subtly different receptors

• Those containing GluA2 subunits have very low Ca2+ permeability

• Activation of all AMPA receptors leads to an influx of Na+, but receptors are only permeable to Ca2+ in Abscence of GluA2

Kainate receptors

GluK4 and 5 don’t form function receptors alone, must be both

NMDA receptors

• cation channel for Na+ and Ca2+

• Channel opening = depolarisation

• Acriviation requires binding of a glutamate (orthosteric site) and a co-agonist (modulatory site)

• Has a voltage sensitive Mg2+ block which is present usually, but removed when cell depolarises

Mg2+ block

• in order for block or NMDAR to occur, the channel must be open e.g. glycerine and glutamate bound

• As membrane potential is depolarised, the block os progressively removed

Coincidence detector:

• AMPARs often present at the same synapses as NMDARs

• Activation of AMPARs depolarises the membrane sufficiently to remove Mg2+ block

• Ca2+ entry through NMDARs is dependant on pre/postsynaptic elements being activate at the same time

• NMDAR is the coincidence detector

Main g-protein subtypes

• Gas

• Gai/o

• Gaq

• Gby

Metabotropic glutamate receptor subunits

Structure of mGlu receptors

• bi-lobed N-terminal contains glutamate binding site

• Cysteine rich domain involved in maintaining tertiary structure

• 7 transmembrane domains

• Second intracellular loop involved in G-protein coupling and determining transduction mechanism

Properties of mGlu receptors

• depending on subtype, can be pre/postsynaptic elements being synaptically localised

• Play a modulatory role in synaptic trasnmission

• Post-synaptic group 1 receptors mediate slow depolarisation (EPSPs)

• Presynaptic groups 2 & 3 decrease NT release

• Desirable targets fro drug discovery

• Modulation of signalling through K+ and Ca2+ → control of excitability of neurons

GABAa receptors

• anion channel (cL-). Channel open = hyperpolarisation

• 5 subunits- 2 alpha, 2 beta, gamma

• Isomers have different sensitivity to alcohol

• Found synaptically (short term) and extra-synaptically (modulating tone of neural circuits)

• Sedative/hypnotic drugs enhance GABAa receptor activity via the modulatory site

GABAergic synaptic transmission (GABAa)

• synaptic transmission = fast

• CL- detected by GABAa creates an IPSP (hyperpolarisation)

GABAb receptors

• dimer made of two 7 transmembrane domains Second intracellular subunits held together by coil interactions between C-terminus tails

• Activation occurs when GABA binds to extracellular domain of B1 subunit

• Located pre and postsynaptically

• GPCR that couples through Gi/Go

Coactivation of GABAa and GABAb

• produces long-lasting biphasic IPSPs

• Synchronous release of GABA results in the simultaneous activation of both receptors

Neuromodulation: alcohol

• alcohol affects neural function, full spectrum of effects is unclear currently

Can modulate glutamatergic neurotransmission:

• non-competitive antagonist (-ve allosteric modulator) → NMDA and AMPA receptors (Ionotropic) decreasing effect

• Reduced glutamate release from presynaptic terminal → increases activity of mGluR2/3

Ethanol effects on NMDA currents

→ ethanol inhibits NMDA mediated currents

• Ethanol dose dependently reversibly inhibits NMDA-induced inwards currents in cultured neurons (voltage clamp)

• Other studies indicate ethanol is a non-competitive antagonist

• Different glutamate receptor subunits have different ethanol sensitivity, which explains why areas of the brain are affected differently to alcohol

Alcohol effects on glutamate transmission

• acutely inhibits glutamate neurotransmission

• Reduced activity of the neuron, no/fewer nerve signals generated

• Chronic alcohol intake leads to compensatory adaptations in neurotransmission of glutamate = excessive activity of the neuron

Behavioural effects of alcohol

→ mediated by changes in glutamatergic signalling

• Acute (reduced signalling) = amnesia, memory loss (intact NMDA signalling required for memory formation)

• Chronic/withdrawal (enhanced signalling) = seizures/brain damage/excitotoxicity, anxiety, disorientation (hyper excitability associated with withdrawal)

Foetal alcohol syndrome

• maternal alcohol levels impair glutamatergic signalling in the developing brain

• Reduced NMDA receptors in offspring

• Developmental and cognitive impairment

Alcohol modulating GABAergic transmission

• ethanol modulates GAABAergic neurotransmission

• Positive allosteric modulator = enhances Cl- influx through GABAa receptors

• Enhanced GABA release = acting via presynaptic GABAb receptors

Chronic exposure to alcohol: GABAergic transmission

• chronic exposure leads to a recused impact on GABAergic transmission

• Change in GABAa receptor subunits composition

• Reduced sensitivity of GABAa to alcohol/neurosteriods

• No change in receptor number

Behavioural effects of alcohol: GABA

→ alcohol mediates chances in GABAergic signalling

Acute (reduced signalling) = sedative, anxiety-reducing, impaired coordination

Chronic/withdrawal (enhanced signalling) = alcohol tolerance (changed subunit composition) and seizures/tremor (hyper excitability due to loss of inhibitory tone)