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Biochemistry of neurotransmitters
Dr. Mamoun Ahram
Neuroscience
2014
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References
• This lecture
• Mark’s Basic Medical Biochemistry, 4th ed, pp. 908-918
• http://what-when-how.com/neuroscience/neurotransmitters-the-neuron-part-1/
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What is a neurotransmitter?
• A chemical substance that:
– Is synthesized and stored in a presynaptic neuron (the enzymes needed for its synthesis must be present in the neuron),
– Is released at a synapse following depolarization of the nerve terminal (usually dependent on influx of calcium ions),
– binds to receptors on the postsynaptic cell and/or presynaptic terminal,
– elicits rapid-onset and rapidly reversible responses in the target cell,
– Is removed or inactivated from the synaptic cleft.
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Types of neurotransmitters
• Small-molecule
– Amines (acetylcholine, epinepherine, dopamine, histmaine, etc.)
– Amino acids (glutamate, aspartate)
• Neuropeptides
• Gases (nitric oxide)
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Note the differences
• Onset and duration of action
• Concentration for action and receptor binding
• Concentration of [Ca+] for release
• Site of synthesis, modification
• Fate
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NEUROPEPTIDES
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Introduction
• More than 50 neuropeptides have been described
– Behavior
– Pain perception
– Memory
– Appetite
– Thirst
– Temperature
– Homeostasis
– Sleep
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Neuropeptides: neurohormones or
neurotransmitters?• Neurohormones: when neurons secrete their
peptides into the vascular system to be transported to a relatively distant target
• Neurotransmitter: Many axon terminals of neurosecretory cells secrete their products at the synapse to directly affect a post synaptic cell
• Neuropeptides can do both – depends on nerve terminal
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Stages of action
• Synthesis (ER and Golgi apparatus)
• Packaging into large-dense core vesicles (with modifying enzymes)
• Transport (fast-axonal transport)
• Release
• Action (prolonged)
• Termination by diffusion and degradation
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Synthesis is sequential
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Synthesis is tissue-specific
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Synthesis is controlled by alternative
splicing
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Role of calcium
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Neuropeptides
• The endogenous opiates
• Neuropeptide Y
• Galanin
• Pituitary adenylate cyclase–activating peptide (PACAP)
• Melanocyte-stimulating hormone (MSH)
• Neurokinin A (NKA)
• Substance P (SP)
• Neurotensin
• Calcitonin-gene–related protein (CGRP)
• Vasoactive intestinal polypeptide (VIP)
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Substance P
• Member of tachykinins family
• 11-amino acid peptide
• Act via neurokinin receptors 1, 2, or 3 (GPCR) and Gs
• Functions: vasodilation, inflammatory response, pain perception
• Pathological connection: eczema, fibromyalgia, GI infection
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Nerve growth factor (NGF)
• Member of the neurotrophin family
• 118-acid polypeptide hormone
• Act via tyrosine kinase receptors
• Affect tissue immune reactivity
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Neuropeptide Y
• A 36 amino acid peptide
• Acts via G-protein coupled receptors (decrease in cAMP, decrease in Ca+2 , and increase in K+
conductance)
• Function: augments the vasoconstrictor effects of norepinephrine
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SMALL-MOLECULE
NEUROTRANSMITTERS
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Types of small-molecule
neurotransmitter
• Nitrogen-containing molecules
– amino acids and their derivatives
– intermediates of glycolysis and the Krebs cycle (TCA cycle)
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Stages of action
• Synthesis of enzymes
– Cytosol
– ER-Golgi apparatus (packaging into large-dense core vesicles)
• Transport of enzymes (slow and fast-axonal transport)
• Synthesis in pre-synaptic terminal
• Packaging in synaptic vesicles
• Release
• Action (short)
• Termination by diffusion, re-uptake, or inactivation
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mM2 [Ca+] =
uM1 .0[Ca+] =
uM100 -50[Ca+] =
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Synaptic vs. large dense core vesicles
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Role of clathrin and dynamin
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SPECIFIC EXAMPLES OF
NEUROTRANSMITTER SYNTHESIS
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But first, note
• Role of cofactors
– S-adenosylmethionine (methyl transfer)
– Pyrodoxal phosphate (vitamin B6): transamination, decarboxylation
– Tetrahydrobiopterin (BH4)
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TYROSINE-DERIVED
NEUROTRANSMITTERS
Dopamine, norepinephrine, and epinephrine
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Rate-limiting
step
Pyridoxal phosphate vesicular
Vitamin B12 or folate
Diet/
liver
phenylalanine
hydroxylase
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50%
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COMT and MAO
Parkinson’s
disease
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Regulation
• Tyrosine hydroxylase
– Short term
• Inhibition by free cytosolic catecholamines• Catecholamines compete with BH4 binding to enzyme
• Activation by depolarization – Tight binding to BH4 following phosphorylation by PKA, CAM
kinases, PKC
– Long-term (plus dopamine -hyroxylase)
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TRYPTOPHAN-DERIVED
NEUROTRANSMITTERS
Serotonin and melatonin
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BH4
Serotonin
5-hydroxyindoleacetic
acid
urine
Antidepressants ,
called selective
serotonin re-uptake
inhibitors (SSRIs),
like Prozac® inhibit
the reuptake
process resulting in
prolonged serotonin
presence in the
synaptic cleft.
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Melatonin
• Serotonin synthesized in the pineal gland serves as a precursor for the synthesis of melatonin, which is a neurohormone involved in regulating
– sleep patterns
– Seasonal and circadian (daily) rythyms
– Dark-light cycle
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GLUTAMATE AND ASPARTATE
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Glutamate and aspartate
• Nonessential amino acids
• Do not cross BBB
– must be synthesized in neurons
• Main synthetic compartments
– neurons
– glial cells
• Both are excitatory neurotransmitters.
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GABA
glutaminaseGlutamine
synthetase
transaminase1
2
3
-KG
Glu
Dehydro
• Two pathways:
• Glycolysis Krebs cycle Transamination or dehydrogenation
• Glutamine (deamination)
• Another source: aspartate
• Removal
– excitatory amino acid carrier-1 (EAAC1)
– glutamate transporter-1 (GLT-1) and glutamate—aspartate transporter (GLAST)
Synthesis of glutamate
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Sources of glutamate
(supplementary)
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Physiological and clinical
implications• Excitatory amino acids may be involved in learning and
memory processes, as well as motor functions.
• Chronic neuropathological conditions such as amyotrophic lateral sclerosis *ALS+ (also known as Lou Gehrig’s disease).
– degeneration of the motor neurons in the anterior horn of the spinal cord, brainstem, and cerebral cortex.
• Prolonged stimulation of neurons by excitatory amino acids results in neuronal death or injury.
• Overexcitatory effects result in Alzheimer’s disease.
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Aspartate
• A vesicular uptake mechanism for aspartate has not yet been demonstrated, somewhat weakening the case for considering aspartate to be a neurotransmitter
• Precursor: oxaloacetate (transmamination)
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Glycine
• The major inhibitory neurotransmitter in the spical cord
• Synthesized from serine by serine hydroxymethyltransferase through 3-phosphoglycerate
• Removal: high-affinity transporter
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OTHERS
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GABA
• GABA is present in high concentrations (millimolar) in many brain regions.
– These concentrations are about 1,000 times higher than concentrations of the classical monoamine neurotransmitters in the same regions.
• The GABA shunt is a closed-loop process with the dual purpose of producing and conserving the supply of GABA.
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GABA shunt
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Diet
Membrane
PL
Synthesis of acetylcholine
• Choline + acetylcoenzyme-A by choline acetyltransferase in cytoplasm
• Transported into and stored in vesicles.
• Removal: hydrolysis by acetylcholinesterase
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Histamine
• it does not penetrate the blood—brain barrier and, hence, must be synthesized.
Pyridoxal phosphate
AstrocytesNeuron
X
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Inactivation of histamine
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Nitric oxide (NO)
• Glutamate is released (1) and acts on NMDA receptors located on the post-synaptic neuron (2)
• Ca2+ enters the postsynaptic neuron and binds with calmodulin activating NOS (3) resulting in formation of NO and citrulline from L-arginine (4).
• No stimulates guanylate cyclase forming cGMP (5), which results in a physiological response (6)
• No can diffuse out: a) to the presynaptic terminal (7) prolonging effect and b) into adjacent neurons (8) and glial cells (9) stimulating guanylate cyclase
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Is NO a neurotransmitter?
• Yes, but:
– It is not stored in vesicles
– It is not released by calcium-dependent exocytosis (it diffuses)
– Its inactivation is passive (there is no active process that terminates its action)
• It decays spontaneously
– It does not interact with receptors on target cells
• Its sphere of action depends on the extent to which it diffuses, and its action is not confined to the conventional presynaptic-postsynaptic direction.
– NO acts as a retrograde messenger and regulates the function of axon terminals presynaptic to the neuron in which it is synthesized.
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Nitric oxide (NO)
• Half-life: 2-4 seconds
• NO is inhibited by hemoglobin and other heme proteins which bind it tightly
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NO synthase
• Isoform I (nNOS or cNOS)
– Neurons and epithelial cells
– activated by the influx of extracellular calcium
• isoform II (iNOS)
– Macrophages and smooth muscle cells
– induced by cytokines
• and isoform III (eNOS)
– Endothelial cells lining blood vessels
– activated by the influx of extracellular calcium
• All three isoforms require BH2 as a cofactor and nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme