neurotransmission and the neuromuscular junction

electrochemical neurotransmission

conversion of electrical signal to chemical signal at the synapse

synaptic neurotransmission - electrochemical coupling at the synapse

1. action potential reaches and depolarises axon terminal

2. depolarisation activates voltage gated, pre synaptic Ca²⁺ channels

3. localised calcium entry triggers fusion of synaptic vesicles to membrane, and exocytosis of neurotransmitters (NTs) from vesicles into the synaptic cleft

4. NTs diffuse into synaptic cleft

5. NTs bind to active receptors on the post synaptic membrane, eliciting response

6. NTs are inactivated

neurotransmitters

small rapid acting messengers

generally, neurons release one type of major NT

• acetylcholine, glutamate - generally considered to be excitatory

• GABA, glycine, serotonin - generally considered to be inhibitory

• noradrenaline

each NT has specific receptors

neurons may express receptors for multiple NTs

neurotransmitter lifecycle

1. precursor uptake e.g. amino acid

2. NT synthesis

3. NT uptake into vesicles

4. NT release into synaptic cleft

5. receptor binding - post synaptic and pre synaptic cell

6. inactivation of NT

ionotropic receptors

ligsnd gated ion channels

NT binding opens the channels; ion flow through

involved in fast synaptic transmission

metabotropic receptors

also known as G protein coupled receptors (GPCR)

NT binding activated G-protein that either modifies function of ion channels or triggers intracellular signalling

involved in slower synaptic transmission

mediated short term as well as long term effects (e.g. gene expression)

neurotransmitter inactivation mechanisms

1. inactivated/degraded by enzymes in the synaptic cleft

2. taken up by presynaptic neuron via transporter protein

3. taken up by glial cell

4. diffuses away into periphery

neurotransmitter examples

acetylcholine

dopamine (DA)

noradrenaline (NA)

adrenaline (A)

serotonin (5-HT)

histamine

glutamate (L-Glu)

y-amino-butyric acid (GABA)

glycine (L-Gly)

glutamate

major excitatory neurotransmitter in the brain

essential neurotransmitter in synaptic plasticity, learning and memory, and higher processing

excessive glutamate signalling can cause excitotoxicity

inactivation - removed from the synaptic cleft primarily by astrocytes that express glutamate transporters

glutamate receptors

four glutamatergic ionotropic receptors (GIuR)

• N-methyl-D-aspartate (NMDA) receptors

• AMPA

• kainate

• delta

eight glutamatergic metabotropic receptors

• mGluR1-8

glutamate excitatory NT

the NT as an excitatory synapse depolarizes the post synaptic membrane e.g. glutamate and NMDA receptor

GABA

major inhibitory neurotransmitter in the CNS - counterbalances action of glutamate

two types:

• GABA_A: ionotropic, ion channels are permeable to Cl-

• GABA_B: metabotropic

inactication: reuptake into pre-synaptic neuron (or astrocytes) by GABA transporters (GAT)

GABA inhibitory NT

the NT at an inhibitory synapse hyperpolarizes the post-synaptic membrane e.g. GABA and GABA_A receptor

Acetylcholine

major CNS NT for consciousness (arousal), learning and memory

In the PNS

• regulates all motor transmission at the neuromuscular junction

• regulates autonomic nervous system

inactivate by acetylcholinesterase (AChE)

botulinum toxin (Botox) blocks the release of acetylcholine from pre synaptic neurons

cholinergic receptors

receptors activated by binding of acetylcholine

nicotinic (nAChR) cholinergic receptors

also activated by nicotine

ionotropic (fast responses)

• ion channels are permeable to Na⁺, Ca²⁺ , K⁺

• excitatory

N_M type at the skeletal neuromuscular junction

N_N type on all postganglionic ANS cell bodies

muscarinic (mAChR) cholinergic receptors

also activated by mushroom poison muscarine

G protein-coupled metabotropic receptors - slower acting effects

5 types (M1-M5)

most cholinergic pathways in the CNA involve muscarinic receptors

neuromuscular junction

action potential propagates along the motor neuron to axon terminal

local calcium influx (voltage gated Ca²⁺ channels) triggers release of the neurotransmitter ACh into the synapse

ACh diffuses across synaptic cleft and binds to nicotinic ACh receptors on the motor end plate (muscle fiber)

ACh binding triggers opening of ligand gated ion channels. Na enters muscle fiber (small efflux of potassium) = end plate potential

if the threshold of -50mV reached → action potential is initiated and propagates across muscle fiber → muscle contraction

ACh is degraded in the synaptic cleft of Acetylcholinesterase

end plate potential

An EPP partially depolarizes the the muscle membrane

multiple/ simultaneous EPPs i.e. release of multiple ACh vesicles, are required to push the muscle above the action potential threshold and generate an action potential