Neurotransmitters are endogenous chemicals that transmit signals between neurons. The major categories are small-molecule neurotransmitters like acetylcholine and amino acids, and large peptides. They act on ligand-gated ion channels or G protein-coupled receptors. After release, they are typically removed from the synapse by reuptake back into the presynaptic neuron or breakdown by enzymes. Examples include acetylcholine, which activates nicotinic and muscarinic receptors, and glutamate, the main excitatory neurotransmitter in the brain. GABA is the primary inhibitory neurotransmitter and binds GABAA/B/C receptors. Neuropeptides are longer amino acid chains that modulate synaptic transmission.

1. Neurotransmitters
Ravish Yadav

2. INTRODUCTION
• Neurotransmitters are endogenous chemicals that transmit signals
from a neuron to a target cell across a synapse
• Synapses are the junctions where neurons release a chemical
neurotransmitter that acts on a postsynaptic target cell, which can be
another neuron or a muscle or gland cell
• Some chemicals released by neurons have little or no direct effects
on their own but can modify the effects of neurotransmitters. These
chemicals are called neuromodulators.

3. Criteria That Define a Neurotransmitter

4. Identified neurotransmitters and neuromodulators can be divided
into two major categories:
SMALL-MOLECULE TRANSMITTERS
Monoamines (e.g., Acetylcholine, Serotonin, Histamine),
Catecholamines (Dopamine, Norepinephrine Epinephrine)
Amino Acids (e.g., Glutamate, GABA, Glycine).
LARGE-MOLECULE TRANSMITTERS.
Include a large number of peptides called neuropeptides including
substance P, enkephalin, vasopressin, and a host of others.
There are also other substances thought to be released into the synaptic
cleft to act as either a transmitter or modulator of synaptic transmission.
These include purine derivatives like Adenosine, Adenosine Triphosphate
(ATP) and Nitric Oxide (NO).

5. Neurotransmitter receptors
Two broad classes:
LIGAND-GATED ION CHANNELS
Open immediately upon neurotransmitter binding
G PROTEIN–COUPLED RECEPTORS.
Neurotransmitter binding to a G protein–coupled receptor induces the
opening or closing of a separate ion channel protein over a period of
seconds to minutes. These are “slow” neurotransmitter receptors.
Each ligand has many subtypes of receptors : selective effect at different
sites

6. DESENSITIZATION
Prolonged exposure to their ligands causes most receptors to
become unresponsive. This can be of two types:
Homologous desensitization, with loss of responsiveness
only to the particular ligand and maintained responsiveness
of the cell to other ligands
Heterologous desensitization, in which the cell becomes
unresponsive to other ligands as well.

7. Reuptake
• From the synaptic cleft back into the cytoplasm of the neuron
The reuptake systems employ families of transporter proteins:
Members include transporters for norepinephrine, dopamine,
serotonin, GABA, and glycine, as well as transporters for proline,
taurine, and the acetylcholine precursor choline. In addition, there may
be an epinephrine transporter.

8. Reuptake is a major factor in terminating the action of
transmitters, when inhibited, the effects of transmitter release
are increased and prolonged. This has clinical consequences.
Glutamate uptake into neurons and glia is important because
glutamate is an excitotoxin that can kill cells by overstimulating
them. There is evidence that during ischemia and anoxia, loss of
neurons is increased because glutamate reuptake is inhibited.

9. Acetylcholine
Acetylcholine, which is the acetyl ester of choline which is released by
many PNS neurons & by some CNS neurons.
It is a excitatory and inhibitory neurotransmitter at different synapses.

10. • Acetylcholine is the transmitter at the neuromuscular junction, in
autonomic ganglia, and in postganglionic parasympathetic nerve-
target organ junctions and some postganglionic sympathetic
nerve-target junctions.

11. • Cholinergic neurons actively
take up choline via a
transporter. Choline is also
synthesized in neurons.
• The enzyme choline
acetyltransferase is found in
high concentration in the
cytoplasm of cholinergic
nerve endings. Acetylcholine
is then taken up into synaptic
vesicles by a vesicular
transporter (VAChT).
• Removed via Hydrolysis to
choline and acetate, a
reaction catalyzed by the
enzyme
ACETYLCHOLINESTERASE.

12. Acetylcholine Receptors
Muscarinic
Nicotinic
M1 M2
NN
NM
M3

13. Catecholamines/biogenic amines
• Norepinephrine, Epinephrine, & Dopamine
• The chemical transmitter present at most sympathetic postganglionic
endings is norepinephrine. It is stored in the synaptic knobs of the
neurons that secrete it in characteristic small vesicles that have a dense
core.
• NOREPINEPHRINE and its methyl derivative, EPINEPHRINE, are
secreted by the adrenal medulla
Most of biogenic amines binds to metabotropic receptors and results in
excitation or inhibition depending on type of receptor.

14. Catabolism of Catecholamines
• Removed from the synaptic cleft by binding to postsynaptic
receptors, binding to presynaptic receptors , reuptake into the
presynaptic neurons, or catabolism. Reuptake is a major mechanism
in the case of norepinephrine.
• Epinephrine and norepinephrine are metabolized to biologically
inactive products by oxidation and methylation. The former reaction
is catalyzed by MAO and the latter by catechol -O –
methyltransferase (COMT).

15. α & β Receptors
• Epinephrine and norepinephrine both act on and receptors, with
norepinephrine having a greater affinity for α-adrenergic receptors
and epinephrine for β-adrenergic receptors.
• G protein-coupled receptors, and each has multiple forms

16. Amino acids:
• Several amino acids are neurotransmitter in the CNS.
(A)Glutamate(glutamic acid)
• The amino acid glutamate is the main excitatory transmitter
in the brain and spinal cord( 75% of the excitatory
transmission in the brain. )
• Uptake into neurons is the main mechanism for removal of
glutamate from synapses

17. (B)GABA
• Major inhibitory mediator in the brain.
• Formed by decarboxylation of glutamate . The enzyme glutamate
decarboxylase (GAD), is present in nerve endings in many parts of
the brain.

18. GABA Receptors
• Three subtypes of GABA receptors have been identified: GABAA,
GABAB, and GABAC
• Increases in Cl– influx and K+ efflux and decreases in Ca2+ influx all
hyperpolarize neurons.

19. (C)Glycine
• Glycine has both excitatory and inhibitory effects in the CNS.

20. ATP & OTHER PURINES:
• Ring structure of the adenosine portion of ATP called purine ring.
• Adenosine itself and monophosphate, diphosphate ,triphosphate
derivatives (AMP, ADP,ATP) is an excitatory neurotransmitter in CNS &
PNS

21. NITRIC GAS/NO
• It is synthesized from arginine, a reaction catalyzed in the brain by
one of the three forms of NO synthase.
• It is estimated that More than 2% of neurons produce it.
• NO is an important cellular signaling molecule. It helps
modulate vascular tone, insulin secretion, airway tone,
and peristalsis, and is involved in angiogenesis and neural
development.
• Unlike other neurotransmitters NO is not previously synthesized
and stored. NO is formed on demand and act immediately because
it’s a very reactive radical.
• It activate secondary messenger called cGMP

22. • Nitric oxide is mediated in mammals by the calcium-
calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS
(neuronal NOS).
•
• The inducible isoform, iNOS, is involved in immune response, binds
calmodulin at physiologically relevant concentrations, and produces
NO as an immune defense mechanism.

23. Neuropeptides:
• Neurotransmitters consisting 3 to 40 amino acids linked by peptide
bonds called Neuropeptides.
• They are numerous & widespread in CNS & PNS.
• Bind to metabotropic receptors and cause excitatory or inhibitory
actions based on which types of receptor it bind.
• Neuropeptides act as hormones also & regulate physiological
processes in body.

24. •Substance P & Other Tachykinins:
• Substance P is a polypeptide containing 11 amino acid residues
that is found in the intestine, various peripheral nerves, and many
parts of the CNS.
• It is one of a family of 6 mammalian polypeptides called
tachykinins that differ at the amino terminal end but have in
common the carboxyl terminal sequence.
• Substance P is found in high concentration in the endings of primary
afferent neurons in the spinal cord, and it is probably the mediator at the
first synapse in the pathways for pain transmission in the dorsal horn.
• In the intestine, it is involved in peristalsis & also a potent vasodilator.

25. Opioid Peptides
Peptides that bind to opioid receptors are called opioid peptides.
The ENKEPHALINS are the is a pentapeptide involved in regulating nociception in
the body.
The enkephalins are termed endogenous ligands, as they are internally derived
and bind to the body's opioid receptors. found in nerve endings in the
gastrointestinal tract and many different parts of the brain, and they appear to
function as synaptic transmitters.
They are found in the substantia gelatinosa and have analgesic activity when
injected into the brain stem. They also decrease intestinal motility.
RECEPTORS
• µ , κ , δ
• All three are G protein-coupled receptors, and all inhibit adenylyl cyclase.
• Activation of µ receptors increases K+ conductance, hyperpolarizing central
neurons and primary afferents. Activation of κ and δ receptors closes Ca2+
channels.