3.3.1 Neurotransmitter and synaptic physiology
Transmitter Synthesis, Storage, Release and Uptake
Synthesis:
An effective synaptic transmission demands very close control of neurotransmitter concentration in the synaptic cleft. The neurons are developed in a sophisticated way and they have the ability to synthesize, package, release and degrade neurotransmitters in order to achieve the required level of transmitter molecule. Neurotransmitter synthesis starts within the pre-synaptic terminals. The enzymes that are required for neurotransmitter production are synthesised within the neuron cell body and after that, they will be transported toward the synaptic vesicles of the nerve terminal at a rate of 0.5-5 mm a day, caused by a mechanism known as slow axonal transport.
Storage and release:
Synaptic vesicles are small sacs where neurotransmitters are stored. When the action potential moves down toward the axon synaptic vesicles present within the pre-synaptic terminal will fuse with the synaptic membrane and through this process, they will release the contents into the synaptic cleft. Neurotransmitter is released into the synaptic cleft when a cell membrane fuses with vesicles. Exocytosis is a process, where neurotransmitters are released in less than a millisecond. Neurotransmitters once within the synaptic cleft diffuse, and engage with the designated receptors on the post-synaptic neurons.
Depending on the action of the neurotransmitter the action propagated could be excitatory or inhibitory:
- Excitatory synapses at the post-synaptic neurons are depolarized.
- Inhibitory synapses at the post-synaptic neurons are hyperpolarized.
An action potential can be generated in the next neuron following enough post-synaptic changes within an excitatory synapse. This process is referred to as facilitation. If multiple presynaptic terminals provide additional input to generate an action potential, then this is called spatial summation.
Neurotransmitters in a resting state are stored inside the vesicles present at the pre-synaptic terminal. There are two types of synaptic vesicles one is small (50nm diameter) and the other is large (70-200nm diameter). The release of neurotransmitters occurs in quantal units because each vesicle has a certain amount of transmitter. In active zones, vesicles are concentrated dense bodies where neurotransmitters are released in the pre-synaptic membrane. At resting position, small numbered vesicles are at active zones. Synapsin I and actin are present near the active zones. Synapsin I is a protein that binds with the actin, connected with the vesicle membrane. Cytoskeletal filament plays an important part in holding the vesicle in position.
Uptake:
In neurotransmitter uptake, (which is the cessation of the action of the neurotransmitter) the neurotransmitter is transported back into the pre-synaptic neuron. At the cleft, the neurotransmitter undergoes enzymatic breakdown via a COMT or MAO-A enzyme. Once the remaining molecules are within the pres-synaptic neuron they are removed by glial cells or via plasma circulation. This process of uptake will inactivate and recycle the neurotransmitters. However, this process does not take place in the transmission of cholinergic synaptic.
| Neurotransmitter: | Examples: |
| Amino acids | GABA Glutamate Glycine |
| Monoamines | Adrenaline Acetylcholine Dopamine Histamine Noradrenaline Serotonin |
| Peptides | Cholecystokinin Endorphins Ghrelin Leptin Neuropeptide Y Neurotensin |
Ion Channels and Calcium Flux in Relation to Synaptic Physiology
Ion channels:
Three main types of ion channels:
- Extracellular ligand-gated
- Intracellular ligand-gated
- Voltage-gated
Another term used interchangeably for ligand-gated is ionotropic. This is when the binding of a chemical messenger alters the opening of the transmembrane channel or pore.
Ionotropic, ligand-gated or ion channel receptors are for these purposes all the same. Ion channels result in a rapid response. Examples include:
- GABAA
- NMDA
- 5HT3
Ion channels are constructed of four or five protein subunits. In the example of GABA-A receptors structure, it is often described as appearing ‘rosette-shaped’. Each individual protein subunit is made up of a string of amino acids which loop in and out of the cell membrane a total of four times. Within the middle of the amino acid string, there are a total of four sites where phosphorylation can occur. Finishing on the extracellular side there is an N-terminal, referring to the free amine group (-NH2).
Calcium flux:
Calcium (Ca2+) is considered important in the excitatory neurotransmitter release process. Blocked or inhibited Ca2+ channels can inhibit the release of neurotransmitters. Ca2+ channels are only open when an action potential goes towards the nerve terminal. This action potential causes Ca2+ to rush toward the neuron terminal due to the presence of a higher extracellular concentration level. Ca2+ concentration levels rise 1000-fold, ranging from 100 nanomolar to 100 micromolar within microseconds following an action potential. Following this, the neurotransmitter is rapidly released. As opposed to inhibitory neurotransmitter action which leads to the entry of Cl–(Purves, 2009).
References:
(1) Brady, S.T., Siegel, G.J., R Wayne Albers and Price, D.L. (2012). Basic neurochemistry : principles of molecular, cellular, and medical neurobiology. Waltham, Massachusetts ; Oxford: Academic Press / Elsevier.
(2) Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., LaMantia, A.-S., McNamara, J.O. and S Mark Williams (2009). Neuroscience.