Neurotransmitters Flashcards
Neurotransmitter groupings
- Classical – active reuptake, synthesized at synapse, stored in small(er) vesicles.
a. Biogenic amine
b. (modified) Amino acid - Peptide
- Others: nitric oxide (gas), cannabinoids (lipids), ATP (nucleotides), adenosine (nucleosides) – know that these exist.
Glutamate is the predominate excitatory neurotransmitter in the brain and spinal cord. The primary inhibitory neurotransmitter in the brain is GABA, while that in the spinal cord is glycine.
Major Biogenic Amine Neurotransmitters in the Central Nervous System (CNS)
Dopamine (DA) Norepinephrine (NE) (a.k.a. noradrenaline) Serotonin (5-HT) Acetylcholine (ACh) Histamine Epinephrine (a.k.a. adrenaline) Others (e.g. tyramine, octopamine)
Major (modified) Amino Acid neurotransmitters
Glutamate (Asparate)
Gamma-Amino Butyric Acid (GABA)
Glycine
Receptors are named after the neurotransmitter in the case of GABA and glycine, but not for the ionotropic forms of glutamate receptors (e.g., NMDA, AMPA, kainate)
Source of dopamine
substantia nigra par compacta (SNc) and ventral tegmental area (VTA)
Source of epinepherine
locus coeruleus (LC), much smaller amounts in lateral pontomesencephalic tegmentum
source of serotonin
raphe nuclei (there are multiple subdivisions)
source of histamine
tuberomammilary nucleus of the posterior hypothalamus
source of acetylcholine
septal nuclei, nucleus basalis of Meynert, reticular formation, lesser amounts in interneurons of caudate and putamen (striatum)
source of glutamate
major excitatory neurotransmitter in brain and spinal cord projection neurons. Used by most neurons in cerebral cortex sending projects to other parts of cortex, brain stem and spinal cord.
Source of GABA
principle inhibitory neurotransmitter of interneurons in the brain. GABAergic neurons in striatum project to the substantia nigra pars reticulata (SNr). GABAergic projections neurons also present in globus pallidus and Purkinje cells of cerebellum.
Source of Glycine
principle inhibitory neurotransmitter of interneurons in the brain stem and spinal cord.
Peptides Neurotransmitter classifications
Pituitary peptides Brain-gut peptides Opioids (produce analgesia) – enkephalins and dynorphins (widely distributed), and endorphins (localized distribution) Neurohypophyseal hormones Hypothalamic-releasing hormones Circulating hormones Others
Catecholamine Biosynthesis Overview
Phenylalanine-> Tyrosine-> L-DOPA-> Dopamine-> Norepinephrine-> Epinephrine
Catecholaminergic neurotransmitters share a common biosynthetic pathway.
The amino acid tyrosine is the biosynthetic precursor and it is taken up into the brain by active transport.
The enzyme tyrosine hydroxylase (TH), which adds a hydroxyl group to tyrosine, is the rate limiting enzyme in catecholamine biosynthesis. In essence, this means that it determines the level of catecholamines. Tetrahydrobiopterin (BH4) is a cofactor. The activity of TH is decreased by end-product inhibition via displacement of a tetrahydrobiopterin cofactor. Phosphorylation of TH increases its activity by allowing it to overcoming end-product inhibition.
Catecholaminergic cells are often identified as being positive for the enzyme tyrosine hydroxylase. Aromatic amino acid decarboxylase (AAAD) is an enzyme involved in biosynthesis of neurotransmitters having tyrosine or tryptophan (e.g., serotonin, 5-HT) precursors. Its cofactor is pyridoxal phosphate (vitamin B6).
Dopamine-beta-hydroxylase (DBH) is the only biosynthetic enzyme located inside synaptic vesicles. It transforms DANE.
Phenylethanolamine-N-methyltransferase (PNMT) has a very restricted distribution in the brain (highest concentrations in parts of the hypothalamus), brainstem (reticular formation, periaqueductal gray, floor of the fourth ventricle) and in the central part of the adrenal gland.
Catecholamine Metabolism Pathway
Phenylalanine (Phe hydroxylase)-> tyrosine
Tyrosine (Tyr hydroxylase)-> dihydroxyphenylalanine (L-DOPA)
L-DOPA (aromatic AA decarboxylase)-> dopamine
dopamine (dopamine beta-hydroxylase)-> norepinepherine
norepinepherine (phenylethanolamine-N-methyl transferase)-> epinepherine
homovallinic acid formation
HVA is formed as a metabolic byproduct of dopamine and can be used to determine dopamine levels in the brain and be used to diagnose brain cancer
dopamine (monoamine oxidase B)-> 3,4-dihydroxyphenylacetaldehyde
3,4-DHPA (aldehyde dehydrogenase)-> 3,4 dihydroxyphenyl acetic acid (DOPAC)
DOPAC (catechol-O-methyltransferase aka COMT)-> homovanillic acid (HVA)
VMAT
vesicular monoamine transporter (VMAT) pumps neurotransmitters from the cytosol into synaptic vesicles. Its has very promiscuous substrate specificity.
VMAT-1 localized in adrenal gland cells
VMAT-2 localized in catecholaminergic, serotoninergic and histaminergic neurons
- DA, NE, 5HT, and histamine (HA) are all packaged by VMAT2
- Acetylcholine has its own transporter (VAChT)
Reserpine
inhibit VMAT-2 and thus “depletes” neurons of vesicular neurotransmitters available for release.
tetrabenazine
inhibit VMAT-2 and thus “depletes” neurons of vesicular neurotransmitters available for release.
Types of NT release
Calcium-dependent (stimulus-dependent) vesicular release
Reversal of catecholamine transporters such as (DAT, NET and SERT).
Dendritic release (calcium-independent)
Indoleamine Biosynthesis Overview
Tryptophan (tryptophan hydroxylase)-> 5-hydroxytryptophan
5-HTP (aromatic AA decarboxylase)-> serotonin
Serotonin (other steps)-> Melatonin
Indoleamine biosynthesis and metabolism has much in common with the catecholamines: amino acid precursor, rate–limiting hydroxylase (ring hydroxylation), AAAD and MAO-type metabolism.
Two genotypically distinct isoforms of tryptophan hydroxylase have been discovered
A. TPH1 is expressed in gut, pineal gland, spleen, thymus
B. TPH2 is predominantly expressed in the brain stem