Neuropeptides and their modulators

A neurotransmitter is a messenger released from a neuron at an anatomically specialised

junction, which diffuses across a narrow cleft to affect one or sometimes two postsynaptic
neurons, a muscle cell, or another effector cell. A neuromodulator is a messenger released from a
neuron in the central nervous system, or in the periphery, that affects groups of neurons, or
effector cells that have the appropriate receptors. It may not be released at synaptic sites, it often
acts through second messengers and can produce long-lasting effects. The release may be local
so that only nearby neurons or effectors are influenced, or may be more widespread, which
means that the distinction with a neurohormone can become very blurred. A neurohormone is a
messenger that is released by neurons into the haemolymph and which may therefore exert its
effects on distant peripheral targets. It may differ only in degree from a neuromodulator in the
extent of its action.

Neuromodulation is the physiological process by which a given neuron uses one or more
chemicals to regulate diverse populations of neurons. This is in contrast to classical synaptic
transmission, in which one presynaptic neuron directly influences a single postsynaptic partner.
Neuromodulators secreted by a small group of neurons diffuse through large areas of the nervous
system, affecting multiple neurons. Major neuromodulators in the central nervous system
include dopamine, serotonin, acetylcholine, histamine, and norepinephrine.

Neuromodulation can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-

synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a
significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the
activity of several other neurons in the brain. For this reason, some neurotransmitters are also
considered to be neuromodulators, such as serotonin and acetylcholine.[1]

Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the
transmitter acts on local postsynaptic receptors, but in neuromodulation, the receptors are
typically G-protein coupled receptors while in classical chemical neurotransmission, they
are ligand-gated ion channels. Neurotransmission that involves metabotropic receptors (like G-
protein linked receptors) often also involves voltage-gated ion channels, and is relatively slow.
Conversely, neurotransmission that involves exclusively ligand-gated ion channels is much
faster. A related distinction is also sometimes drawn between modulator and driver synaptic
inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus
causing that spiking.
Neuromodulation is the targeted release of a substance fom a neuron that either alter the efficacy
of synaptic transmission or the cellular properties of a pre and postsynaptic neuron (or glial cell)
via metabotropic receptor.

Modulators are the neurotransmitter neuropeptide hormones that have spatially distributed
temporally extended effect on the recipient neuron and circuts.

Neuromodulators are the subset of neurotransmitter that are released in a diffused

manner(volume transmission)

An entire neural tissue may be subjected to the neuromodulation action due to exposure. These in
turn can tune the neural circuitry of the entire brain region. Each modulatory system is the locus
of particular chemical transmission that is projected to broad area of the brainstream, thalamus
and cortex. The origination of this system is sub cortical. All of these neuromodulatory system
are reciprocally connected with frontal cortex and parts of limbic system. The modes of
modulation are intrinsic and extrinsic.

Comparison between Neurotransmitters and Neuromodulators

Classical neurotransmitters Neuropeptides

Type of Small water-soluble molecules
Molecule containing amine (amino
acid transmitters) and
carboxyl groups
Biosynthesis Synthesized from dietary
precursors by specific
enzymes,
mainly in nerve terminals, in
some cases in perikarya
Storage In small vesicles
Transport Synthesizing enzymes as well
as storage vesicles
tranported down the axon
Release Occurs through exocytosis at
specialized regions (active
zones) from the nerve terminal
Possibility of paracrine action No
Large molecules
Transcripted and translated
from prepropeptides genes.
Then, after
activation by peptidases,
transformed in propeptide and
finally, after
activation of converting
enzymes, neuropeptide is
obtained. This occurs
in the cell body
In large vesicles
Only storage vesicles
transported down the axon
Occurs through exocytosis,
but no specific active zones
Yes
 Inactivation Metabolism in synaptic cleft Catabolism by specific
or reuptake by transporter peptidase, no reuptake, no
and recycling recycling

Classification of Neuromodulators

Hundreds of neuromodulators are secreted in our body and may be classified in many ways.On
the basis of size of the molecule they can be classified into two broad categories-

1. Small molecule neurotransmitters-they can be further categorized into

Amino acids-glutamate and aspartate are excitatory while GABA and glycine are
inhibitory in action.

Ach found at the neuromuscular junction and is having two main receptors nicotinic and
muscarinic.

Purines-ATP , adenosine

Biogenic amines-Dopamine, serotonin,histamine, norepinephrine

2. Neuropeptides

Opioids- Enkephalin, B-endrophine

Tachykinin-substrate P neurokinin

Posterior pituitary-vasopressin, oxytocin

Pancreatic-neuropeptide Y

Neuropeptides are small proteins that act on cells surface to communicate between
neurons.They regulate physiological processes throughout all phases of development. They act
as neurohormones, neurotransmitters, and/or neuromodulators, maintain homeostasis and
influence cognitive, emotional and behavioural functions, including hunger, thirst, sex drive,
pleasure and pain

Many different peptides evoke specific effects on behaviour. For example, oxytocin is involved
in social behaviours, including bonding and maternal behaviour, and vasopressin acts in the brain
to affect social recognition and aggression. Other nerve cells release other peptides and they have
effects on other emotions and behaviours. Evidence of the hormonal nature of the behaviour
effects of peptides comes from experiments involving gene manipulation, either through
transgenic mutations or viral gene transfer, showing that behavioural traits accompany alterations
in the distribution of peptide receptor expression. Thus, it appears that it is not the distribution of
fibres of peptidergic neurons in the brain that determines particular behaviours, but the
distribution of the peptide receptors. .

One such neuropeptide is neuropeptide Y. Neuropeptide Y (NPY) found in brain is made up of

36 amino acids. It regulates food intake memory and learning process anxiolytic effect. Most of
the work regarding the action of NPY has been done on a free living non-parasitic nematode i.e.
Caenorhabditis elegans. It is having a nervous system with cerebral ganglia.

Apart from its role in feeding control, NPY is involved in the regulation of luteinizing hormone,
adrenocorticotropic hormone and insulin secretion, reduction of growth hormone release,
anxiolysis, and thermoregulation. NPY causes long-lasting vasoconstriction inskeletal muscle,
heart, kidney, and brain. Presynaptically, NPY inhibits its own release as well as the release of
noradrenaline and ATP, and suppresses synaptic inhibition mediated by GABA receptors.
Additionally, NPY enhances memory retention, and is also involved in the modulation of ethanol
consumption and resistance. Several disorders and pathological conditions are associated with
altered NPY functions.

Role of Neuropeptide Y as an anticonvulsant in controlling eplileptic seizures

A neuronal network in this disease is developed. Gamma aminobutyric acid (GABA)

hypoactivity induces dopamine hyperactivity because dopaminergic neurons are affected by the
inhibitory influence of the GABAergic system through GABA(A) receptors. Glutamate
hyperactivity is exerted via presynaptic N-methyl-D-aspartate (NMDA) receptors, which
strongly inhibit serotoninergic neurons, and via postsynaptic ionotropic glutaminergic receptors,
which can induce epileptic seizures. Depending on their mechanism of action, anticonvulsant
drugs in clinical use may be divided into three groups: those drugs which facilitate gamma-
aminobutryic acid (GABA)ergic neurotransmission; those which block neuronal ion channels;
and those whose mechanism of action is unresolved. The compounds acting on GABAergic
systems may be further subdivided into those which modulate transmission through chloride
channels, e.g. the barbiturates and the benzodiazepines; those compounds, in particular
vigabatrin, which reduce the degradation of GABA by blocking GABA transaminase; and those
which inhibit the re-uptake of GABA into the presynaptic terminal. The other group of
compounds whose mechanism of action is known are those which block neuronal ion channels.
Blockage of voltage-operated sodium channels by lamotrigine, phenytoin or carbamazepine
leads to decreased electrical activity and, probably, a subsequent reduction in glutamate release.
Conversely, ethosuximide, blocks voltage-operated calcium channels, especially those which
mediate calcium currents in thalamic neurones. Of those drugs in which the mechanism of action
is unknown, sodium valproate is the prime example. An antagonistic action at the N-methyl-D-
aspartate (NMDA) subtype of glutamate receptor might also be a possibility, which could be the
case with some of the newer compounds currently undergoing evaluation.

Neuropeptide Y is a 36 amino acid peptide which has been suggested to act as an endogenous
anticonvulsant.NPY is a powerful endogenous modulator of limbic seizure activity.It has potent
inhibitory effects on excitatory synaptic transmission from stratum radiatum to CA1 pyramidal
cells and in both area CA1 and CA3 of hippocampus. In an experiment done on mice those
lacking NPY had an enhanced susceptibility to PTZ(pentylene tetrazole)-induced seizures
suggesting that the peptide is an important modulator of excitability in the CNS.
Six different NPY receptor subtypes have been reported (Y1Y6). In the central nervous system,
and specifically in hippocampus (an epileptogenic brain region), expression of Y1, Y2 and Y5 are
most prominent. All three subtype receptors have been shown to influence epileptic
activity.Ghrelin may exert modulator effects on neurotransmission.It enhances NPY and GABA-
ergic activity in the brain. Ghrelin is a 28 amino acid peptide with growth hormone-releasing and
appetite-inducing activities.Ghrelin is involved in many more processes than was initially
postulated, and its endocrine, paracrine and autocrine effects play a role in its physiological and
pathophysiological functions .

Graphical representation of NPY mRNA production when NPY injected exogeneously

Influence of exogenous neuropeptide Y (NPY) on NPY mRNA and protein expression in the
hippocampus of rats with chronic epilepsy. The data are presented as mean SEM(scanning
electron microscopy) and were analyzed by the Student-Newman-Keuls (test in which different
samples are compared) test in which four different groups aP < 0.05, vs. control grsoup; bP <
0.05, vs. kainic acid (KA) and adeno-associated viral-empty (rAAV) groups. 2, 3, 4 wk: 2, 3, and
4 weeks after vector injection (A) NPY mRNA expression in the rat hippocampus was detected
by quantitative PCR(Polymerase chain reaction). The threshold cycle (Ct) data of each target
gene were normalized to the internal control gene, glyceraldehyde-3-phosphate dehydrogenase
(GAPDH). A comparative Ct method was applied to calculate relative quantification (RQ), which
was used in the final statistical analyses. (B) NPY protein expression in rat hippocampus was
detected by western blot analysis. The expression of NPY is presented as the relative absorbance
rate between NPY and -actin.
[Anti-epileptic effects of neuropeptide Y gene transfection into the rat brain
Changzheng Dong1, Wenqing Zhao2, Wenling Li3, Peiyuan Lv4, Xiufang Dong5 ]

References

NPY Receptors Blockade Prevents Anticonvulsant Action

of Ghrelin in the Hippocampus of Rat
Mina Ghahramanian Golzar, 1 Shirin Babri, 1 , 2 Zohre Ataie, 1 Hadi Ebrahimi, 1 Fariba Mirzaie, 1 and Gisou
Mohaddes 1 ,2 ,*
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