Neurotransmitters

Hello, this is the first post in a series about neurophysiology. Today we'll take a look at a variety of  neurotransmitters, how they are produced and the effects they have on postsynaptic neurons. We'll compare electric and chemical synapses as well as how small molecule and peptide neurotransmitters are made. We'll also discuss inotropic and metabotropic receptors. Enjoy!
 

 Chemical and Electrical Synapses

Nerves have two methods of communicating with each other: through electrical synapses and through chemical synapses. With electrical synapses, which are very fast, electrical signals are transmitted through gap junctions directly between neurons and are present mainly in the brain. With chemical synapses, one neuron secretes a neurotransmitter which binds to receptors on the plasma membrane of the second cell. This is the most common way in which neurons communicate with each other as well as with effector organs (eg. Muscles and glands). Chemical synapses can have inhibitory or excitatory post synaptic potentials.

Small-Molecule Neurotransmitters

The synthesis of these neurotransmitters happens in the presynaptic terminals. The enzymes required for synthesis are produced in the cell body of the neuron and reach the presynaptic terminal by slow axonal transport. The precursor molecules of the neurotransmitters are either produced locally or enter the nerve terminal through specific transporters. The neurotransmitters are then synthesised by the enzymes and packaged into vesicles. Once the neurotransmitter has been exocytosed, some of the molecules may re-enter the presynaptic terminal to be used in the synthesis of more neurotransmitters.

Peptide Neurotransmitters

The synthesis  of this type of neurotransmitter occurs in the cell body of the neuron. Here, enzymes and polypeptides are packaged into vesicles in the Golgi apparatus and are sent to the presynaptic terminal by fast axonal transport along microtubules. While these substances are being transported, the propeptides are modified by enzymes and this forms neurotransmitters. Once the neurotransmitters have been exocytosed they are degraded by enzymes. Thus, no recycling is possible.

Acetylcholine (ACh)

Acetylcholine is a small molecule neurotransmitter and so is produced in presynaptic terminals. It is synthesised from acetyl-CoA and Choline, a process which is catalysed by Choline acetyltransferase, and packaged in vesicles. The arrival of an action potential at the presynaptic terminal causes an influx of calcium ions into the cell. These calcium ions cause the vesicles to fuse with the cell membrane and ACh is exocytosed into the synapse. Here, ACh binds to muscarinic and nicotinic receptors on the effector cell membrane as well as the presynaptic terminal itself. Acetylcholine is then broken down into acetate and choline by acetylcholinesterase.

Acetylcholine has both inotropic, which are ligand-gated, and metabotropic receptors, which are G-protein coupled receptors. Nicotinic acetylcholine receptors are inotropic, non-selective ion channels which allow more sodium ions to enter the cell than potassium ions to exit. This leads to depolarisation of the cell membrane. Nicotinic acetylcholine receptors (nAChRs) are activated by nicotine, which behaves as an agonist, and are blocked by curare. They belong to a superfamily of ligand-gated ion channels and have two subtypes: skeletal muscle (nAChR_m) and neuronal subtypes (nAChR_n). Acetylcholine is excitatory to skeletal muscle but may be excitatory or inhibitory at other sites.

 Muscarinic acetylchoine receptors are metabotropic and mediate cholinergic autonomic responses. They are activated by muscarine and are blocked by plant alkaloids such as atropine. Several subtypes exist and they have a structure which is similar to all other metabotropic receptors.

Glutamate

Glutamate is a non-essential amino acid that cannot cross the blood-brain barrier and thus is produced from glutamine released from glial cells. Glutamine is taken up by a system A transporter (SAT2) on the presynaptic terminals and is then converted to glutamate by glutaminase. Glutamate can also be synthesised locally from glucose by the transamination of α-ketoglutarate which comes from the Kreb’s cycle. In the neurons, vesicular glutamate transporters (VGLUT) load glutamine into vesicles. After it has been released into the synapse, glutamate is recycled back to glial cells by excitatory amino acid transporters (EAATs) where it is converted to glutamine.

Glutamate has both inotropic and metabotropic receptors. All inotropic glutamate receptors are excitatory and have a structure similar to nicotinic acetylcholine receptors. There are three subtypes: AMPA, NMDA and Kainate and are glutamate-gated cation channels that allow the passage of sodium and potassium ions. In addition, NMDA receptors allow the passage of calcium ions which act as a second messenger to activate intracellular signalling cascades. The NMDA receptors have glutamate, antagonist, magnesium and phenylcyclidine binding sites. The magnesium binding site is voltage dependent and at resting membrane potential magnesium blocks the passage of other ions, especially calcium. When the cell membrane is depolarised, however, it allows ions to flow through the channel. Thus NMDA can only be activated when the cell has been depolarised. There are also three metabotropic classes which have varied physiological roles.   

γ-Aminobutryic Acid (GABA)

Most of the inhibitory synapses in the brain use GABA as a neurotransmitter and is most common in local circuit neurons and the cerebellum. In the synaptic terminal glucose is converted to glutamate which is then converted to GABA which is stored in vesicles. When GABA is released into the synapse it attaches to GABA receptors on the post synaptic neuron. It is also transferred into adjacent glial cells and back into the presynaptic neuron by the sodium dependent GABA transporter (GAT). Once GABA is returned to the cell it may be packaged into vesicles or broken down to glucose.

There are three subtypes of GABA receptors and all are inhibitory: GABA_A and GABA_C are inotropic while GABA_B is metabotropic. The inotropic GABA receptors are GABA-gated ion channels which let chloride ions into the cell. This leads to hyperpolarisation and inhibition of the post-synaptic neuron. GABA receptors have separate binding sites for GABA and various drugs such as benzodiazepine, barbiturates and steroid anaesthetics. Drugs don’t open the channel but change the effect that GABA has on it when they bind at the same time.

Catecholamines

Catecholamines regulate many brain functions and are also active in the peripheral nervous system. All are excitatory.

Dopamine

Dopamine is a neurotransmitter found in several regions of the brain. In the presynaptic terminal dopamine is packaged into vesicles by VMAT2 (Vesicular monamine transporter). Once dopamine is released into the synapse, it may attach to D1/D2 receptors on the surface of the post synaptic cell and this causes an effector response. Alternatively it is taken up by the presynaptic neuron by the sodium dependent dopamine transporter (DAT) which terminates its synaptic action or it is taken up by the post synaptic neuron. Dopamine may also attach to a D2 autoreceptor on the surface of the pre-synaptic neuron. Dopamine acts by activating metabotropic receptors; it is generally excitatory but may be inhibitory at some sites.   

Dopamine receptors may be blocked by domperidone and acepromazine.

 Norepinephrine (Noradrenaline)

Noradrenaline is also a catecholamine derived from dopamine and may be excitatory or inhibitory. In the presynaptic terminal, after dopamine has been packaged into vesicles by VMAT2 it is converted to noradrenaline by dopamine β-hydroxylase. Noradrenaline is then secreted into the synapse where it activates alpha and beta adrenergic G-protein coupled receptors on the post synaptic neuron. It may also bind to α2 prejunctional receptors which inhibit the formation of vesicles in the presynaptic terminal. Noradrenaline may also be taken up by both the pre- and post- synaptic neurons.

Xylazine, a veterinary tranquiliser, stimulates the α2 presynaptic receptor which inhibits the release of noradrenaline and produces a tranquilising effect. Meanwhile, some antidepressant drugs as well as amphetamines prevent the uptake of noradrenaline and this increases its levels in the synapse.

 

Epinephrine (Adrenaline)

Adrenaline is also a catecholamine but is present in lower amounts and in fewer neurons than the others. Epinephrine acts on both alpha and beta adrenergic receptors and is excitatory. It is synthesised in a similar way to norepinephrine except that it is synthesised by phenylethanolamine-N-methyltransferase.

 

Serotonin

Serotonin is synthesised from tryptophan and is also known as 5-hydroxytryptamine (5-HT). It has an excitatory effect on post-synaptic neurons. Serotonin is packaged into vesicles and once it is secreted into the synapse it binds to post synaptic serotonin receptors and pre synaptic serotonin receptors. It may also be taken up by the presynaptic neuron by the serotonin reuptake transporter (SERT) and this terminates its effects in the synapse. Serotonin reuptake inhibitors (SSRI’s), which include many antidepressant drugs, inhibit the reuptake of serotonin by SERT.

Many serotonin receptors exist and most are metabotropic. The only inotropic one is the 5-HT₃ receptor. In humans, serotonin receptors are involved with the emotions, circadian rhythms, motor behaviours and mental arousal.

 

Neuropeptides

Many neuropeptides behave as neurotransmitters. Some are involved with emotions, others (substance P and opioids) are involved in the perception of pain, and other regulate the responses to stress.

Opioids

Opioid peptides are endogenous compounds which mimic the actions of morphine and their effects are mediated by metabotropic peptide receptors. Importantly, their receptors are activated at very low concentrations. Generally , they have a depressant activity.

Nitric Oxide

Nitric oxide (NO) is a lipid soluble gas, thus it is freely diffusible through tissues, and has a very short half-life. It stimulates the enzyme guanylate cyclase which results in the formation of cGMP which mediates many of the physiological effects of NO. It is generated by nitric oxide synthase (NOS) which comes in various forms including neuronal, inducible and endothelial types (nNOS, iNOS and eNOS, respectively).

 

The synthesis of Nitric Oxide is related to the synthesis and secretion of glutamate. When glutamate binds to NMDA receptors on the postsynaptic neuron it results in an influx of calcium ions. These calcium ions bind to calmodulin and the calcium-calmodulin complex activates nNOS which results in the formation of NO. Nitric oxide then activates cGMP in the postsynaptic neuron, glial cells and adjacent neurons.

 

Importantly, nitric oxide is not stored in vesicles as it is generated as it is needed and it is not released by calcium-dependent exocytosis, it freely diffuses across the cell membranes. Nitric oxide also decays spontaneously and its action is not confined to the postsynaptic membrane. In addition, it behaves as a retrograde messenger and regulates the function of the axon terminals presynaptic to the neuron in which it is produced.

That’s it for this post, if you have any questions please don’t be afraid to ask :)