Neurotransmitters
Neurotransmitters
A chemical released by one neuron that affects
another neuron or an effector organ
(e.g., muscle, gland, blood vessel)
• Excitatory neurotransmitters
– cause depolarization
• Inhibitory neurotransmitters
– cause hyperpolarization
Attributes of “classical” neurotransmitters
 Synthesized in the presynaptic cell
 Stored in membrane-bound vesicles
(synaptic vesicles)
 Released from the presynaptic vesicle in
response to membrane depolarization
 Induction of a physiological response in the
post synaptic cell (by depolarizing or
hyperpolarizing its membrane)
 inactivated (rapidly) in the synaptic cleft
Classification of neurotransmitters
GROUP
amines
amino acids
purines
gases
peptides
EXAMPLES
acetylcholine (Ach),
norepinephrine, epinephrine,
dopamine, 5-HT
glutamate, GABA
ATP, adenosine
nitric oxide
endorphins, tachykinins, many
others
Excitatory/inhibitory neurotransmitters
EXCITATORY
Acetylcholine
Norepinephrine
Epinephrine
Glutamate
Aspartate
Histamine
INHIBITORY
GABA
Glycine
MIXED
Dopamine
Serotonin
Release of neurotransmitters
Neurotransmitters bind to receptors
Ionotrophic receptors: these act as ion
channel themselves to produce their effects.
Metabotrophic receptors:
these activate
second messenger system (cAMP, PIP3) to
produce their effects.
biogenic amines
Neurotransmitters – biogenic amines
 Catecholamines
• Dopamine
• Norepinephrine
• Epinephrine
 Indoleamines
• Serotonin (5-HT)
• Melatonin
Catecholamines – functions
Dopamine: control of voluntary movement
(nigrostriatal tract), emotional responses
and memory (limbic system)
Norepinephrine: “fight or flight response” such as
stimulation of heart rate, sweating, skin
vasoconstriction and bronchodilation (sympathetic
nervous system), state of alertness (brain stem)
Epinephrine: response to stress, redirection of blood
from skin to heart, glycogen metabolism, blood
pressure (adrenal medulla under influence of Achcontaining nerves)
Catecholamines - Synthesis
BH4
Tyrosine hydroxylase
BH2
L-Dihyroxyphenylalanine (DOPA)
Dopa decarboxylase
CO2 PLP
Dopamine
O2
++, Vit C
Cu
Dopamine β hydroxylase
Norepinephrine
SAM
Phenylethanolamine
N-methyltransferase
Epinephrine
SAH
ADRENAL MEDULLA
NEURONS
Tyrosine
Vit B12
Folate
Parkinson’s disease
• Degeneration of nigrostriatal dopamine neurons in the
brain resulting in a deficiency of Dopamine
• Symptoms include trembling of hands, arms, legs, jaw
and face; stiffness of the arms, legs and trunk;
slowness of movement; poor balance and coordination
• Treatment with L-DOPA which enters the brain and is
decarboxylated to dopamine.
• L-DOPA is given together with carbidopa, DOPA
carboxylase inhibitor that cannot enter the brain,
preventing unwanted formation of dopamine outside
the brain
Indoleamines – functions
Serotonin: involved with mood, anxiety,
appetite, sleep induction, memory and
learning
Melatonin: involved in response to light-dark
cycle organizing seasonal and circadian
rhythms, regulating reproductive functions
Synthesis – indoleamines
Tryptophan
BH4
Tryptophan hydroxylase
BH2
5’hyroxytryptophan
Dopa decarboxylase
CO2 PLP
Serotonin
Acetyl CoA
CoASH
SAM
Melatonin
SAH
Vit B12
Folate
Degradation–Norepinephrine
Degradation–monoamines
Norepinephrine
epinephrine
MAO-A,-B
COMT
Vanillylmandelic
acid
Dopamine
MAO-B
COMT
Homovanillic
acid
Serotonin
MAO-A
Hydroxyindoleacetic
acid
Endocrine tumors (pheochromocytoma, Carcinoid
syndrome) diagnosed by the measurements of
these breakdown products in urine.
monoamines- release and uptake
Monoamines and depression
•
•
•
“amine theory of depression” states that depression is
caused by a relative deficiency of amine neurotransmitters at central synapses
Prevention of catabolism of catecholamines and
serotonin reduce depression by elevating the levels of
these compounds. MAOA inhibitors act as
antidepressants
Inhibitors of norepinephrine and serotonin transport
into neurons also act as antidepressants (e.g. prozac;
serotonin reuptake inhibitor)
Histamine
Histamine – Functions
•
Dilates blood vessels, increases capillary
permeability, contracts bronchial and intestinal
smooth muscle, stimulates gastric acid secretion
and nasal fluid discharge
Histamine - synthesis and degradation
Acetylcholine
Acetylcholine - functions
•
•
Major neurotransmitter at the neuromuscular
junctions to induce muscle contraction
Play an important role in attention, learning,
reward pathways and memory by reinforcing the
ability to detect and respond to meaningful stimuli
Neurons associated with Ach degenerate
in Alzheimer's disease resulting in
declining language and perception,
confusion and memory loss.
Acetylcholine – synthesis and degeneration
Acetylcholine- release and inactivation
Disorders of acetylcholine metabolism
Myasthenia gravis: a disease characterized by muscle
weakness. Autoimmune disorder due to formation of
antibodies against the nicotinic Ach recptors, preventing
trnsmission of nerve impulses to muscles. Treated by
inhibitors of Ach esterase (pyridostigmine, neostimine) and
corticosteroids
Lambert-Eaton myasthenic syndrome: autoimmune disorder
also characterized by muscle weakness. Due to autoantibodies against the presynaptic voltage-gated calcium
channels
Acetylcholinesterase inhibitors
•
Organophosphate insecticides and nerve gases
(sarin) inhibit acetylcholinesterase resulting in
an excess of Ach, initially causing uncontrolled
muscle contraction and eventually paralysis.
Treatment by atropine.
Amino acids as neurotransmitters
Amino acids as neurotransmitters
Recruited as neurotransmitters by packaging into
synaptic vesicles
Their action is terminated by sodium dependent
high affinity uptake with need for any specific
degradative enzymes
EXICTATORY
Glutamate
Aspartate
INHIBITORY
Glycine
GABA
Glutamate/GABA - synthesis
Inhibitors of Amino Acid NT
Benzodiazapines (valium, Xanax) bind GABA
receptors reducing anxiety, inducing sleep and
guarding against seizures (anticonvulsants)
Barbiturates produce a wide spectrum of effects,
from mild sedation to total anesthesia
by potentiating inhibitory GABA receptors and
inhibiting excitatory AMPA glutamate receptors
Strychnine binds to glycine rectorss leading to
convulsions, spastic contraction of skeletal
muscles and death due to impairment ot
muscles of respiration.
NITRIC OXIDE
NITRIC OXIDE
NO is not stored in vesicles but released directly into
the extracellular space
Functions
• Relaxation of vascular and intestinal smooth
muscle
• Neural transmission
• Regulation of mitochondrial energy production
• Cytotoxic action on parasites and tumor cells
NITRIC OXIDE - synthesis
Peptides
Peptides
Over 80 peptides shown to influence neural
functions
Synthesized as precursor proteins, packaged into
vesicles and cleaved to the active form by peptidases
e.g.
Opioids peptides (endorphins, enkephalins)
Regulate pain and pleasure pathways
Substance P
transmits signals in response to pain
Peptides inhibitors
Opioid receptors are sites of action for morphine
and codeine which are powerful analgesics
Opiates affect pleasure pathways in the brain
resulting in the associated euphoric effects.
Endorphins released after strenuous exercise give
the so-called “jogger's high”
the end!!