Neurotransmitter (NT) and NN M1, M4, M5 – CNS

M2 – Heart
 Substances that mediate chemical signaling M3 – Glands,
between neurons Smooth Muscles
 Site of NT Synthesis: Nerve Terminals Glutamate AMPA, Kainate, mGluR
 Storage of NT: Synaptic Vesicles NMDA
 Criteria for a substance to be considered a NT: GABA GABAA  CNS GABAB CNS
o Must be demonstrated to be present in GABAC retina
the presynaptic terminal Glycine Glycine -
o Must be synthesized by the presynaptic Receptors
cell Norepinephrine - α- and
o Must be released on the depolarization and β-adrenergic
of the terminal Epinephrine receptors
o There should be specific receptors for it (adrenoceptors)
on the postsynaptic terminal (true for Dopamine - D1-like (D1 and
substances that act as synaptic D5)
transmitters) D2-like (D2, D3,
 >100 substances have been identified as and D4)
potential NT Serotonin 5-HT3 5-HT1 , 5-HT2, 5-
 3 major categories of NT: HT4, 5-HT5, 5-HT6,
o Small-molecule Transmitters 5-HT7
 Acetylcholine (ACh) Histamine - H1 - H3
 Amino Acids ATP P2X receptors P2Y and P2U
 Biogenic Amine receptors
 Purine (e.g. ATP) Substance P - Neurokinin
o Peptides (e.g. Substance P, Opioid, etc) receptors (NK1–
o Gaseous Transmitters (e.g. NO, CO) NK3),
*Classic Nonpeptide NT = ACh, Amino Opioid - μ, κ, and δ
Acids, Biogenic Amine Peptides
Other - Essentially
Neuropeptides Metabotrophics
Gas NT - -

*Neurotransmission = general term to describe both

synaptic and nonsynaptic signaling between cells
*Neuromodulators = chemicals released by neurons
that have little or no direct effect on their own but can
modify the effects of NT

I. SMALL – MOLECULE NT
 NT RECEPTORS:
a. Acetylcholine
o Distinguished by pharmacological
Function:
differences in their sensitivity to a
 NT in PNS:
particular agonist or antagonists
o NMJ
o 2 Major Receptor Categories
o Sympathetic and Parasympathetic
 Ion-Linked Receptors or
Ganglia
Ionotrophic Receptors
o Postganglionic Fibers from
 G-protein linked or
Parasympathetic ganglia and few
Metabotrophic Receptors
sympathetic ganglia
 NT in CNS: *Ach is an NT released by all
NT Ionotrophic Metabotrophic
neuron that exits the CNS
Acetylcholine: Nicotinic Ach Muscarinic Ach
o Neurons in Brainstem nuclei
Receptors: NM Receptors:
 o Neurons in Basal Forebrain complex
(septic nuclei and nucleus basalis)
projecting to neocortex,
hippocampus, and amygdala
o Neurons in Pontomesencephalic
cholinergic complex, projecting in
dorsal thalamus and forebrain
o Neurons in basal ganglia
o Spinal Cord
o May be involved in memory,
learning, and sleep-wake states
Synthesis:
 Sythesized in the cytoplasm of cholinergic
presynaptic neuron terminals
 Choline = transported from the extracellular
space into the nerve terminal via a Na+-
dependent choline transporter (CHT)
Post-synthesis:
 Following synthesis, it is transported from
the cytoplasm into vesicles by a vesicle-
associated transporter (VAT).
 Acetylcholine is released when a nerve
impulse triggers the influx of Ca2+ into the
nerve terminal
Reuptake:
 Acetylcholinesterase – enzyme that terminates
the action of ACh, once ACh is released.
o Aka True or Specific
Acetylcholinesterase
o Concentrated in synaptic cleft
o Removal process:
 Hydrolysis of ACh by
Acetylcholinesterase into
Choline and Acetate in the
Synaptic cleft
 Choline is taken up by Na+
symporter in the presynaptic
membrane for ACh resynthesis
*Othere Cholinesterases – non-specific to ACh
e.g.: Pseudocholinesterase – can hydrolyze ACh
but has different property; under endocrine
control, and affected by liver function.
Increased in cases of organic pesticide
poisoning
B. Excitatory and Inhibitory Amino Acids
i. Glutamate - EXCITATORY
Function:
 Major excitatory CNS NT
 Present in all cells and has a key role in
multiple metabolic pathway
 Precursor to GABA
 Causes depolarization
 Potent neurotoxin at high concentration
Synthesis:
 2 distinct synthesis pathway:
o α-ketoglutarate produced by
the Krebs cycle is converted to
glutamate by the enzyme GABA
transaminase (GABA-T).
o In the second pathway,
glutamate is released from the
nerve terminal into the synaptic
cleft by Ca2+-dependent
exocytosis and transported via
a glutamate reuptake
transporter into glia, where it is
converted to glutamine by the
enzyme glutamine synthetase.
Glutamine then diffuses back
into the nerve terminal where it
is hydrolyzed back to glutamate
by the enzyme glutaminase.
ii. GABA – INHIBITORY
- Produced from Glutamate
- Released from many local interneurons,
spiny of the striatum, Purkinje cells of
cerebellar cortex
*Purkinje Cells containing GABA is surprising
since PC comprises the whole of cerebellar
cortex function. Therefore, cerebellar cortex
function is to inhibit/suppress the activity of
 downstream targets (cerebellar and - involve in setting the level of arousal (sleep and
vestibular nuclei) waking), attention and mood
- improved in homeostatic function (ANS) and
motor system
Function:

 Major inhibitory NT of all nervous system

 Mediates both presynaptic and
postsynaptic inhibition
i. Catecholamine

Synthesis: Synthesis:

 GABA, which exists as β-aminobutyrate in

the body fluids, is formed by
decarboxylation of glutamate by the
enzyme glutamate decarboxylase (GAD)
 GAD is present only in neurons that use
GABA as a transmitter

Reuptake:

 GABA is metabolized primarily by

transamination (via GABA-T) to succinic
semialdehyde and then to succinate in the
citric acid cycle
 An active reuptake of GABA via the GABA
transporter. A vesicular GABA transporter
(VGAT) transports GABA and glycine into
secretory vesicles.
iii. Glycine – INHIBITORY AND EXCITATORY
- Antagonize by strychnine
Function:
 Inhibitory NT in restricted territories
 Acts as co-transmitter at NMDA-type
glutamate receptors = makes the receptors
more sensitive to Glutamate
 Acts by increasing Cl- conductance
C. BIOGENIC AMINES
- have roles outside the nervous system; often acts
as hormones
 Tyrosine is formed from Phenylalanine
thru Phenylalanine via Phenylalanine
hydroxylase but usually is from diet
 Rate limiting step in the pathway is the
conversion of tyrosine to DOPA
therefore, the rate limiting enzyme is
Tyrosine hydroxylase
 Norepinephrine is the only small-
molecule transmitter that is synthesized
in synaptic vesicles instead of being
transported into the vesicle after its
synthesis.
READ THIS NOTE:
NOT ALL TYROSINE WILL BE CONVERTED TO
EPINEPHRINE JUST BECAUSE THE PATHWAY
POINTS THEM TO!!! To understand the pathway
better:
 If a neuron is a Dopaminergic, this
pathway terminates when Dopamine is
produced
  If a neuron is a Noradrenergic, this *Psychosis – due to hyperactivity of
pathway terminates when dopaminergic synapses; can be treated by
Norepinephrine dopamine antagonists (chlorpromazine and
 Epinephrine is produced via other antipsychotic drugs), which inhibit
methylation of norepinephrine dopamine receptors in the postsynaptic
membrane

Reuptake / Removal: ii. Serotonin

 Via Na+Cl- dependent transporter - Highest concentration in blood platelets

 Degraded by monoamine oxidase (MOA) and GIT (enterochromaffin cells and
and catechol O-methyltransferase myenteric plexus
(COMT) - Serotoninergic Fibers arise in raphe nuclei
 Metabolite of MOA: 3,4-dihydroxymandelic
acid and its glycol  Synthesis:
o If Norepinephrine and epinephrine: :
vanillylmandelic acid (VMA), and 3-
methoxy-4-hydroxyphenylglycol
o If Dopamine: 3,4-Dihydroxyphenylacetic
acid and homovanillic acid (HVA)
 Metabolite of COMT:
o Normetanephrine and
Metanephrine  VMA
o HVA

 Synthesized from Tryptophan

a) Norepinephrine (Noradrenaline) and
Epinephrine (Adrenaline)
- Both are secreted also in adrenal medulla
- Norepinephrine is present at most
sympathetic post-ganglionic endings
- Noradrenergic neurons are found in locus
cereleus and nucleus subcoeruleus
- Noradrenergic Neurons  norepinephrine-
secreting neurons
- Adrenergic Neurons  may also be applied
to Noradrenergic Neurons but must be
reserved for Epinephrine-secreting neurons
 Rate-limiting Step: Conversion of Trytophan to
5-hydroxytryptophan
 Rate-limiting Enzyme: Tryptophan hydroxylase
Reuptake / Removal:
 SERT – serotonin transporters (SERT)
 Once recaptured by SERT, it is either taken back
into the vesicle or inactivated by MAO to
become 5-hydroxyindoleacetic acid (5-HIAA)

iii. Histamine

b) Dopamine - Histaminergic neurons are located within

- Dopaminergic Neurons arise from 2 brainstem tuberomamillary nucleus of hypothalamus
regions: - Found in cells of gastric mucosa and in mast
o Nigostriatal System / Substantia cells
nigra pars compacta – involved in
motor control Synthesis:
o Mesocortical System / Ventral
Tegmental Area – involved in  Formed from decarboxylation of Histidine
reward behavior, addiction,
psychiatric disorders
D. PURINES  Released by neurons and act on receptors
I. ATP throughout the CNS
- found in all synaptic vesicles and is co-released  Co-released by NT but can function as a sole or
in during synaptic transmission primary NT at a synapse
- mediate rapid synaptic responses in the ANS  Synthesized at the cell body (not in presynaptic
and a fast response in habenula terminal)
(See page 102 of Berne-Levy Physiology or pages
Reuptake/Removal: 153-154 of Ganong for detailed classes of
neuropeptides, take attention to Opioid Peptides,
 ATPase and 5-nucleotidase to Substance P, and Other Polypeptides )
adenosine
 Adenosine is then recycled by the
presynaptic terminal III. GAS NEUROTRANSMITTER

 Newest form of NT
II. PEPTIDES  Neither packed into synaptic vesicles nor
released by exocytosis
 Consists of 3-40 amino acids  Synthesis is triggered by depolarization
 >100 neuropeptides are identified  Highly permeant and simply diffuse from the
nerve terminal to the neighboring cells
 Destroyed by diffusion or binding to superoxide
anions or various scavenger proteins  no
specific reuptake mechanisms, nor they
undergo enzymatic destructions
 DO NOT BIND TO A RECEPTOR but can still
influence cell activity such as enzyme activation,
nitrosylation, etc.

A. Nitric Oxide (NO)

 NT of CNS and NT of synapses between

inhibitory motor neuron of ENS and GIT
smooth muscles
 Activate guanylyl cyclase thus a signal
transduction molecule also.
 Play a role in synaptic plasticity and
thus in memory and learning
 Synthesis: NO is produced as a by-
product of oxidation of arginine to
citrulline via the enzyme NO synthase
and the stimulation of cytosolic Ca+2

B. Carbon Monoxide (CO)