Structural Biochemistry/Neurotransmitters

Neurotransmitters
A neurotransmitter is a chemical that is released by a terminal button and has an excitatory or inhibitory effect on another neuron. There are many types of neurotransmitters. There are currently over 100 known agents that serve as neurotransmitters.

A brain circuit is a neurotransmitter current or neural pathway in the brain.

By mimicking a neurotransmitter's effect, agonist will enhance and increase the activity of that neurotransmitter while, on the other hand, antagonist will decreases or blocks the effects of a neurotransmitter.

Another chemical substance calls inverse agonist is responsible for producing effects opposite to those of a particular neurotransmitter. Neurotransmitters Activities:

Neurotransmitters are stored in tiny sacs at the end of the neuron and are released into the synapse as the sacs merge with the outer membrane by an electric jolt. The neurotransmitters travel across the gap to bind with receptors. The neurotransmitters are released from the receptors after the messages has been successfully absorbed by the adjacent neuron. After that, those chemical substances are either degraded or reabsorbed back to the neuron where they come from.

What makes neurotransmitter different from other chemical signaling system?
There are many other signaling system of chemicals such as hormones, neurohormone, and paracrine signaling. However neurotrasmitters have advantages in having a greater degree of amplification and control of the signal. It also lengthens the time of cellular integration from milliseconds to minutes and even hours. While hormones are mainly synthesized in gland, neurotransmitters are synthesized and released from neurons. Neurotrasmitters are, as far as we know, only released in response to an electrical signal. There are many mechanisms that must exist to terminate the action of the neurotrasmitters such as chemical deactivation, recapture (endocytosis), glial uptake and diffusion.

Exocytosis of Neurotransmitters Release
Exocytosis is a process by which vesicles release their contents. Between presynaptic and postsynaptic neurons, certain neurotransmitters are carried out within vesicles from presynaptic neurons are released to the synaptic cleft. In order to do so, first there is an influx of Ca++ ions takes place through voltage gated calcium channels in the presynaptic site. The calcium ions intering the cells affect the movements of the vesicles toward the active sites by dissolving some actin filaments. It also helps the fusion of the vesicles with the plasma membrane in the presynaptic side. As the vesicles fuse, the neurotranmitters are released into the synaptic cleft, then which binds to the corresponding receptors on the postsynaptic neuron.

Categories of Neurotransmitters
Neurotransmitters are separated into two very broad categories based on their size: neuropeptides and small-molecule neurotransmitters.

Neuropeptides
Neuropeptides are generally large molecules that range from 3 to 30 amino acids and consists of over 100 peptides. They are grouped into five categories: brain/gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing hormones, and everything else. Neuropeptides are genetically coded, synthesized from mRNA as prohormones. They are mostly colocalized with and modulate effects of other neurotrasmitters rather than directly presenting the effects. There is no uptake of the NTs, but rather they are broken down by enzymes.

Neuropeptides include large molecules of opioids that include:

1. Beta-Endorphin - made from proopiomelanocortin - produced in pituitary gland, hypothalamus, brain stem

2. Met and Leu Enkephalin - made from proenkephalin - produced throughout brain and spinal cord

3. Dynorphin - ade from prodynorphin - produced throughout brain and spinal cord

Small-Molecule Neurotransmitters
Small-molecule neurotransmitters are much smaller than neuropeptides and may consist of a single amino acid or other molecule. The biogenic amines are a group within the small-molecule transmitters that consists of the catecholamines (dopamine, norepinephrine, epinephrine), serotonin, and histamine.

Definition and function
Acetylcholine is a neurotransmitter that plays a very significant role in the central and peripheral nervous systems. Acetylcholine plays a very big role in the movement of muscles in the peripheral nervous system. Acetylcholine also seems to be released in a variety of areas in the autonomic branch of the peripheral nervous system. In the central nervous system, acetylcholine plays a role in plasticity, arousal, reward, attention, and REM sleep.

Metabolism
The synthesis of acetylcholine takes place in the nerve terminals. This process requires acetyl coenzyme A (also called acetyl CoA) and choline. Acetyl CoA is synthesized from glucose during glycolysis, and choline is already present in plasma. The synthesis of acetylcholine further requires choline acetyltransferase. After the synthesis, the ACh is then loaded into synaptic vesicles and released from the presynaptic terminal to the postsynaptic cell. Acetylcholinesterase (AChE) responds to the released acetylcholine and hydrolyzes the molecules back into choline and acetyl CoA. The choline is then transported back to the presynaptic terminal and recycled to resynthesize new ACh. The cleanup of old acetylcholine is the job of acetylcholinesterase. RCSB PDB Protein of the Month: Acetylcholinesterase

Drugs that affect release of acetylcholine
Two drugs that influence the release of acetylcholine are botulinum toxin and black widow spider venom. Botulinum toxin is produced by a bacteria called clostridium botulinum that grows in improperly canned food. Botulinum toxin inhibits the release of acetylcholine. Black widow spider venom is produced by the black widow spider and it increases the release of acetylcholine.

Receptors
There are two types of receptor sites that are sensitive to acetylcholine.

1. Muscarinic Receptors - It is named so because they are responsive to the drug muscarine. Muscarinic receptors are mostly located in the parasympathetic autonomic nervous system. If a drug is antimuscarnic, that means that it interferes with the role of acetylcholine in stimulating parasympathetic reations of the body. Examples are atropine and scopolamine. Atropine, when applied to the eyes, for examples, causes the pupils to dialte by inhibiting the parasympathetic tendency for the pupils to constrict.

2. Nicotinic Receptors. - They are responsive to nicotine that are found near the end points of motor neurons where skeletal muscles are innervated as well as thourghout the cerebral cortex. Some antinicotinic drugs such as the poison curare, affect these motor neurons so dramatically that the body can become paralyzed.

Glutamate
Glutamate is a key component in normal brain function. It is believed that over half the synapses that occur in the brain release glutamate as a neurotransmitter. It was discovered in 1907 by Kikunae Ikeda and was identified as a neurotransmitter in 1970s by Peter Usherwood. It is an excitatory relative of GABA. An excessive amount of glutamate (usually come from brain damage or a stroke) is very toxic to neurons and may result in brain cell death. Example for disease of excessive glutamate production is ALS, a degenerative neuromuscular disease.

Characteristics of glutamate 1. Glutamate is a principal excitatory neurotransmitter that is biosynthesized as byproduct of glucose metabolism. 2. Excess of glutamate can be neurotoxic. 3. Glutamate has four receptor types: a. NMDA receptor - NMDA is an ionotropic receptor that detects simultaneous events. - The receptor is gated by comnination of voltage and ligand channels. Glutamate plus glycine binding opens channel to Ca++ for influx - The effect mediates learning and memory through long term potentiation that essentially deals with psychological addiction,  behavioral sensitization, and drug craving. b. AMPAa Receptor c. Kainate d. AMPAb

Metabolism
The synthesis of glutamate is done locally from precursors such as glutamine, which comes from glial cells. The glutamine is released into the presynaptic terminal and synthesized into glutamate using an enzyme called glutaminase. The newly synthesized glutamate is then transported from the presynaptic terminal and across the synaptic cleft in synaptic vesicles. After release from the vesicles, the glutamate is then transported to the glial cells and converted into glutamine. This process is called the glutamate-glutamine cycle.



GABA
GABA (or gamma-Aminobutyric acid) is used frequently in inhibitory synapses in the central nervous system. It is most commonly found in local circuit interneurons.

GABA is an inhibiting neurotransmitter which is best known for its ability to reduce anxiety by reducing postsynaptic activity. However, GABA's effect is not only to anxiety but has a broader influence. The GABA system is spread throughout the brain. Different types of GABA receptors seem to act in different ways which leads to the conclusion that GABA is not just one system working in only one manner but is composed of several subsystems.

Metabolism
GABA synthesis requires glucose, which metabolizes to glutamate. An enzyme called glutamic acid decarboxylase (GAD) then converts the glutamate into GABA. GAD requires a cofactor called pyridoxal phosphate to work properly. A deficiency in vitamin B6, in which pyridoxal phosphate is derived from, would prevent the synthesis of GABA from glutamate. After the GABA has been released and used, the GABA is then transported to glial cells via synaptic vesicles specifically for GABA, called GATs. There, the GABA is then converted into succinate.

Glycine
Glycine is a neutral amino acid that is also distributed within the central nervous system. It is synthesized from serine using an enzyme called serine hydroxymethyltransferase and then transported to be released from the pre-synaptic terminal in synaptic vesicles called GATs. After the release of glycine, plasma membrane transporters remove it from the synaptic cleft.

Biogenic Amines
The biogenic amines are sometimes classified as a separate group from the small-molecule neurotransmitters. They regulate many functions of both the central and the peripheral nervous systems. Many psychiatric disorders occur because of defects in the synthesis or the pathways of the biogenic amines. There are five known biogenic amine transmitters: dopamine, norepinephrine, epinephrine (all together known as the catecholamines), histamine, and serotonin. The catecholamines are all synthesized from tyrosine.

Dopamine
Dopamine is most present in the corpus striatum, which plays a key role in the coordination of body movements. It is synthesized from tyrosine with the help of DOPA decarboxylase. It is then transported to the pre-synaptic terminals in synaptic vesicles called vesicular monoamine transporter (VMAT).

A defect in dopamine production is a cause for Parkinson's disease. It is also involved in the reward centers of the brain, and many drugs used for abuse target the dopamine synapses in the central nervous system.

Prostaglandins
A chemical messengers that work right within the cells where they are synthesized.

Structure:It is an unsaturated carboxylic acids derived from arachidonic acid. The numerous functional groups in prostaglandin contribute to its variety functions in the body; there are 2 alkenes group (one cis and one trans), 2 alcohols, a ketone, and one acid on a 20 carbon skeleton with a five-member ring.

Function: It stimulates inflammation process, responds to injury by producing pain or infection by producing  fever. It forms blood clots when blood vessel is damaged. Specific prostaglandins are involved with the induction of labor and reproductive processes.

Norepinephrine
Norepinephrine (or noradrenaline) is used in the locus coeruleus in the brain. It is involved in behaviors related to sleeping, attention, and feeding. The synthesis of norepinephrine requires an enzyme called dopamine-β-hydroxylase to convert dopamine to norepinephrine.

Norepinephrine is a part of the endocrine system that seems to stimulate at least two group of receptors called alpha-adrenergic and beta-adrenergic receptors. In the central and peripheral nervsous system, several norepinephrine circuits have been identified which actively helps our body tp control heart rate, blood pressure, respiration. One of the norepinephrine circuit is associated with the emergency reactions or alarm responses. Thus, it may indirectly plays an important role in panic attacks and other disorders. Norepinephrine is concentrated in the hypothalamus and libic system but also found throughout the brain.

Epinephrine
Epinephrine (or adrenaline) is also found in the brain. It is the least abundant of the three catecholamines in the brain. Epinephrine is mostly located in the medulla, the hypothalamus, and the thalamus. Phenylethanolamine-N-methyltransferase catalyzes norepinephrine to convert it to epinephrine.

Histamine
Histamine is found in the hypothalamus and sends signals to the central nervous system. It is involved in arousal and attention as well as the vestibular system. Histamine is synthesized from the histidine

Serotonin
Serotonin (or 5-hydroxytryptamine) is found in the pons and upper brainstem. It is involved in the regulation of sleep and wakefulness. Serotonin is synthesized from tryptophan.

Serotonergic pathways are a topic of interest when it comes to studies of depression and anxiety. Drugs to treat these disorders often target these pathways.

Serotonin (5-hydroxytrytamine or 5-HT) is a neurotransmitter that is associated with the processing of information and coordination of movement, inhibition, restraint, assists the regulation of eating, sexual, and aggressive behaviors. There are at least 15 different serotonin receptors that play different function in our body. Several of drugs affect the serotonin system. For example, serotonin-specific inhibitors (SSRIs),which enhances serotonin's effects by preventing it from being absorbed, are used to treat particularly anxiety, mood, and eating disorder.

Serotonin is very important to psychopathology because it may involves in different psychological disorders. Low serotonin activity will lead to aggression, suicide, impulsive overeating, excessive sexual behavior. Moreover, Its interaction with dopamine is implicated in schizophrenia.