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Neurotransmitters, Neuroactive Molecules and Associated Enzymes


Neurotransmitters Overview

Neurotransmitters, Neuroactive Molecules and Associated Enzymes

In the central nervous system, the most important way of synaptic transmission is the neurochemical transmission. The neurotransmitter binds to the corresponding postsynaptic membrane receptor immediately after release from the presynaptic membrane, producing a synaptic depolarization potential or a hyperpolarizing potential, resulting in an increase or decrease in postsynaptic nerve excitability. Thereby the chemical signal is converted into an electrical signal transmission. And then the neurotransmitter is immediately inactivated or reused by a series of enzymes. After years of research on neurotransmitters, progress has been made in the mechanisms of regulation of neurotransmitters. Since the transmission of neurotransmitters has been shown to play a role in many neurological diseases, and the further understanding of specific mechanisms are beneficial for the clinical treatment of these diseases.

Mechanism of Neurotransmitters

Ionic neurotransmitters refer to the changes in potential caused by the action of nerve cells through the action of nerve cells and can be divided into excitatory neurotransmitters and inhibitory neurotransmitters according to their effects on the next neuron. The main excitatory neurotransmitters are acetylcholine, norepinephrine, and serotonin. Excitatory neurotransmitters are present in the neutrophils of the presynaptic membrane. When the nerve impulses of the last neuron are transmitted from the axons to the axon terminals, it leads to the permeability of the presynaptic membrane to calcium ions enhanced, allowing calcium ions to flow from the tissue fluid into the cells, thereby increasing the intracellular calcium ion concentration. The neurotransmitter is excreted by exocytosis and release to the synaptic gap. The neurotransmitter gradually diffuses from the presynaptic membrane to the postsynaptic membrane by means of the diffusion of the tissue fluid and realizes the transition of the electrical signal to the chemical signal transmitted by the transmitter. When excitatory neurotransmitters diffuse into the postsynaptic membrane, the neurotransmitter is a chemical information molecule, and the neurotransmitter specifically binds to the receptor on the posterior membrane, causing a potential change in the postsynaptic membrane. Stimulation of excitatory transmitters enhances the permeability of the postsynaptic membrane to sodium ions and allows sodium ions to flow inward. For example, acetylcholine is an excitatory neurotransmitter widely distributed in the central nervous system and plays an important regulatory role in regulating body temperature, learning and memory, and body movement. Mechanisms of inhibitory neurotransmitters: The inhibitory neurotransmitters often involved are dopamine, glycine, and gamma-aminobutyric acid. The process of delivery of inhibitory neurotransmitters is still released from the presynaptic membrane of the previous neuron by exocytosis, and then diffuses, gradually diffuses into the postsynaptic membrane, and binds to receptors behind the synapse. When the inhibitory neurotransmitter contacts the posterior membrane, the carrier channel that transports chloride ions in the postsynaptic membrane is opened, allowing chloride ions to enter the cell from outside the cell, thereby allowing the nerve cell to be negatively charged externally.  The state is further strengthened to form a large potential difference between the inside and outside of the membrane, so that the resting potential is further enhanced, and the resting potential of the next neuron cannot be inferior to the resting potential action potential, otherwise resulting in inability of the posterior membrane to be excited. Gamma-aminobutyric acid (GABA) is an inhibitory transmitter in the brain and plays an important role in sedation, hypnosis and anxiolytic. Studies have shown that anxiety-induced excitement occurs mainly because the nervous system in the brain continues to excite. Abnormal excitement and anxiety are associated with insufficient secretion of inhibitory transmitters. If gamma-aminobutyric acid (GABA) is sufficiently secreted, the excitability of the brain's nerves is inhibited, thereby achieving sedative, hypnotic and anxiolytic effects. Currently, clinical medicine has developed gamma-aminobutyric acid (GABA) as a drug that is used to treat neurological hyperactivity or abnormal excitability and diseases such as excitement, epilepsy, and anxiety. The mechanism of action of the metabolic neurotransmitter receptor is when the neurotransmitter diffuses through the anterior membrane to the postsynaptic membrane, it binds to the metabotropic neurotransmitter on the postsynaptic membrane, and then the signaling is transduced by G protein-coupled family and the G protein. The two signaling pathways achieve cascading amplification benefits that cause the next neuron to excite. This mode is basically independent of changes in potential caused by sodium ions and potassium ions.

Neuroactive Molecules

There are four types of neuroactive molecules in the brain, namely, biogenic amines, amino acids, peptides, and others. Bio-primary amine neurotransmitters are the first to be discovered, including dopamine (DA), norepinephrine (NE), epinephrine (A), and serotonin (5-HT). Amino acid neurotransmitters include gamma-aminobutyric acid (GABA), glycine, glutamic acid, histamine, and acetylcholine (Ach). Peptide neurotransmitters are classified into endogenous opioid peptides, substance P, neurotensin, cholecystokinin (CCK), somatostatin, vasopressin and oxytocin, and neuropeptide y. Other neurotransmitters are classified into nucleotides, arachidonic acid, anandamide, and sigma receptors (sigma receptors). The neurotransmitter between the parasympathetic and effector of a vertebrate is also acetylcholine, but some are excitatory (as in the digestive tract) and some are inhibitory (as in the myocardium). Epinephrine includes norepinephrine (NAD), adrenaline (Ad), and dopamine (DA). The link between the sympathetic ganglion cells and the effector is norepinephrine. Serotonin (5-HT): Serotonin neurons are mainly concentrated in the nucleus of the pons, which is generally inhibitory, but also excitatory. Amino acid transmitter: Glutamate (Glu), γ-aminobutyric acid (GABA), and glycine (Gly) were identified as transmitters. Glutamate is a transmitter of crustacean neuromuscular junctions. Aminobutyric acid is first discovered in the junction formed by the crayfish cheek open muscle and inhibitory nerve fibers. It was later demonstrated that gamma-aminobutyric acid is also a central inhibitor of the transmitter. Synapses with glycine as a transmitter are mainly distributed in the spinal cord and are also inhibitory transmitters. In recent years, it has been found that a plurality of peptides having a small molecule is neuroactive, and neurons contain small peptides, although it is not certain that they are transmitters. As mentioned earlier, synaptic transmission is accomplished by the release of chemical transmitters through the presynaptic membrane. A chemical substance is identified as a neurotransmitter and should meet the following conditions: a pre-synaptic neuron with a precursor substance and a synthetase system capable of synthesizing this transmitter; a transmitter stored in a synaptic vesicle in order to prevent damage by other enzymes in the cytoplasm; when the excitatory impulse reaches the nerve endings, the vesicle inner transmitter can be released into the synaptic cleft; the transmitter acts on the special receptor of the postsynaptic membrane through the synaptic cleft. Electrophysiological microelectrophoresis is used to apply the transmitter ions to the neurons or effector cells, and to simulate the transmitter release process which can lead to the same physiological effects; there are enzymes or other links that inactivate this transmitter. The use of a transmitter mimetic or receptor blocker can potentiate block the synaptic transmission of this transmitter. There are many chemicals in the nervous system, but not necessarily neurotransmitters. Only chemicals that meet or basically meet the above conditions can be considered as neurotransmitters. Regarding neurotransmitters, firstly, it was found in the part of the peripheral vagus nerve that inhibits the heart.

Associated Enzymes

As an indispensable catalyst in the body, enzymes mediate many biochemical reactions and play an important role in the transmission of neurotransmitters. The first is the synthesis of neurotransmitters. Choline and acetyl-CoA synthesized can produce the acetylcholine by the catalysis of alkali acetyl-CoA translocase. Since the enzyme is present in the cytosol, acetyl-CoA can be synthesized in the cytosol, and synthesized and stored by vesicles after synthesis. The synthesis of norepinephrine is based on tyrosine. First, dopamine is synthesized under the catalysis of tyrosine hydroxylase, and then norepinephrine is further synthesized by β-hydroxylase in the vesicle and stored in small bubble. When the transmitter is inactivated, acetylcholine is hydrolyzed by cholinesterase into choline and acetic acid. After norepinephrine enters the synaptic cleft, part of it is taken away by the blood circulation and destroyed in the liver. The other part is destroyed and inactivated by the action of catecholamine methyltransferase and monoamine oxidase in the effector cells. However, most of the norepinephrine is reuptake and reused by the presynaptic membrane. The inactivation of dopamine is like the inactivation of norepinephrine and is also disrupted by the action of catecholamine methyltransferase and monoamine oxidase. Inactivation of peptide transmitters relies on enzymatic degradation, such as by degradation of aminopeptidases, carboxypeptidases, and some endopeptidases. Related enzymes play an important role in the synthesis and degradation of neurotransmitters.

References:

  1. Oukhatar F, Même S, Même W, et al. MRI Sensing of Neurotransmitters with a Crown Ether Appended Gd3+ Complex. Acs Chemical Neuroscience. 2015, 6(2):219.
  2. Gemperline E, Chen B, Li L. Challenges and recent advances in mass spectrometric imaging of neurotransmitters. 2014, 6(4):525-540.
  3. Polo E, Kruss S. Nanosensors for neurotransmitters. Analytical & Bioanalytical Chemistry. 2016, 408(11):2727-2741.
  4. Nutt D J. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008, 69 Suppl E1 (69 Suppl E1):4-7.
  5. Paschou P, Fernandez T V, Sharp F, et al. Chapter Six – Genetic Susceptibility and Neurotransmitters in Tourette Syndrome. International Review of Neurobiology. 2013, 112:155-177.

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