Neurotransmitter Definition
Neurotransmitter is a chemical substance that acts as the mediator for the transmission of nerve impulses from one neuron to another neuron through a synapse.
Table of Contents
Neurotransmitter History
The existence of neurotransmitters was first discovered by an Austrian scientist named Otto Loewi in 1921. He dreamt of an experiment, which he did practically, and came out with this discovery.
Loewi’s Experiment
- He used two frogs for this experiment. The heart of frog A was with intact vagus nerve and was placed in a saline-filled chamber.
- The heart of frog B was denervated and kept in another saline-filled chamber. Both the chambers were connected in such a way that the fluid from chamber of frog A could flow into the chamber of frog B.
Read And Learn More: Medical Physiology Notes
- When vagus nerve of frog A was electrically stimulated, siowing of heart rate was observed. After a short delay, the heart rate in frog B also was found to be slowing down.
- From this observation, Loewi speculated that some chemical substance must have been released from the vagus nerve of frog A, which was responsible for the slowing down of the heart rate in frog B.
- He named it as “Vagusstoff”. Later this chemical substance was considered as a neurotransmitter and called acetylcholine.
Criteria For Neurotransmitter
Nowadays, many substances are categorized as neurotransmitters. To consider a substance as a neurotransmitter, it should fulfill certain criteria as given below:
- The substance must be found in a neuron
- It must be produced by a neuron
- It must be released by a neuron
- After release, it must act on a target area and produce some biological effect
- After the action, it must be inactivated.
Classification Of Neurotransmitters
Depending Upon Chemical Nature: Many substances of different chemical nature are identified as neurotransmitters. Depending on their chemical nature, neurotransmitters are classified into three groups:
- Amino Acids: The neurotransmitters of this group are involved in fast synaptic transmission and are inhibitory and excitatory in action. GABA, glycine, glutamate (glutamic acid), and aspartate (aspartic acid) belong to this group.
- Amines: Amines are modified amino acids. The neurotransmitters of this group involve in slow synaptic transmission. These neurotransmitters are also inhibitory and excitatory in action. Noradrenaline, adrenaline dopamine, serotonin, and histamine belong to this group.
- Others: Some neurotransmitters do not fit into any of these categories. One such substance is acetylcholine. It is formed from the choline and acetyl coenzyme A in the presence of the enzyme called choline acetyltransferase. Another substance included in this category is the soluble gas nitric oxide (NO).
Depending Upon Function: Some of the neurotransmitters cause excitation of postsynaptic neurons while others cause inhibition. Thus, neurotransmitters are classified into two types:
- Excitatory neurotransmitters
- Inhibitory neurotransmitters.
- Excitatory Neurotransmitters
- The excitatory neurotransmitter is the chemical substance that is responsible for the conduction of impulse from the presynaptic neuron to the postsynaptic neuron.
- The neurotransmitter released from the presynaptic axon terminal does not cause the development of action potential in the postsynaptic neuron.
- Rather, it causes some change in the resting membrane potential – slight depolarization by the opening of sodium channels in the postsynaptic membrane and the influx of sodium ions from ECF.
- The slight depolarization is called excitatory postsynaptic potential (EPSP). EPSP in turn causes the development of action potential in the initial segment of the axon of the postsynaptic neuron. The common excitatory neurotransmitters are acetylcholine and noradrenaline.
- Inhibitory Neurotransmitters
- The inhibitory neurotransmitter is the chemical substance that inhibits the conduction of impulse from the presynaptic neuron to the postsynaptic neuron.
- When it is released from the presynaptic axon terminal due to the arrival of the action potential, it causes the opening of potassium channels in the postsynaptic membrane and the efflux of potassium ions.
- This leads to hyperpolarization which is called the inhibitory postsynaptic potential (IPSP). When IPSP is developed, the action potential is not generated in the postsynaptic neuron. The common inhibitory neurotransmitters are gamma-aminobutyric acid (GABA) and dopamine.
Transport And Release Of Neurotransmitter
- The- neurotransmitter is produced in the cell body of the neuron and is transported through the axon. At the axon terminal, the neurotransmitter is stored in small packets called vesicles.
- Under the influence of a stimulus, these vesicles open and release the neurotransmitter into the synaptic deft. It binds to specific receptors on the surface of the postsynaptic cell. The receptors are G proteins, protein kinase, or ligand-gated receptors.
Inactivation Of Neurotransmitter
After the execution of the action, the neurotransmitter is inactivated by four different mechanisms:
- It diffuses out of synaptic cleft to the area where it has no action
- It is destroyed or disintegrated by specific enzymes
- It is engulfed and removed by astrocytes (macrophages)
- It is removed by means of reuptake into the axon terminal.
Reuptake Of Neurotransmitter
Reuptake is a process by which the neurotransmitter is taken back from the synaptic cleft into the axon terminal after execution of its action. The reuptake process involves a specific carrier protein for each neurotransmitter.
Important Neurotransmitters
Some of the important neurotransmitters are described here. Details of neurotransmitters are given in the Tables.
Acetylcholine
- Acetylcholine is a cholinergic neurotransmitter. It possesses excitatory functions. It produces the excitatory function opening the ligand-gated sodium channels.
- Acetylcholine is the transmitter substance at the neuromuscular junction and synapse. It is also released by the following nerve endings.
- Preganglionic parasympathetic nerve
- Postganglionic parasympathetic nerve
- Preganglionic sympathetic nerve
- Postganglionic sympathetic cholinergic nerves:
- Nerves supplying eccrine sweat glands
- Sympathetic vasodilator nerves in skeletal muscle
- Nerves in amacrine cells of retina
- Many regions of brain.
- Synthesis: Ach is synthesized in the cholinergic nerve endings. Synthesis takes place in the axoplasm and Ach is stored in the vesicles. It is synthesized from Acetyl Coenzyme A (Acetyl CoA). It combines with choline in the presence of the enzyme choline acetyltransferase to form Ach.
- Fate: The action of Ach is short-lived. Within one millisecond after the release from the vesicles, it is hydrolyzed into acetate and choline by the enzyme acetylcholinesterase. This enzyme is present in basal lamina of the synaptic cleft.
- Acetylcholine Receptors
- There are two types of receptors through which Ach acts on the tissues namely, muscarinic receptors and nicotinic receptors. The reason for the terminology of these receptors is as follows:
- The poisonous substance from toadstools called muscarine acts on a specific group of receptors known as muscarinic receptors; similarly, another substance called nicotine acts on a specific group of receptors called nicotinic receptors but, Ach acts on both the receptors.
- The muscarinic receptors are present in all the organs innervated by the postganglionic fibers of the parasympathetic system and by the sympathetic cholinergic nerves.
- Nicotinic receptors are present in the synapses between preganglionic and postganglionic neurons of both sympathetic and parasympathetic systems. The nicotinic receptors are also present in the neuromuscular junction on the membrane of skeletal muscle.
Noradrenaline: It is the neurotransmitter in adrenergic nerve fibers. It is released from the following structures
- Postganglionic sympathetic nerve endings
- Cerebral cortex
- Hypothalamus
- Basal ganglia
- Brainstem
- Locus ceruleus in pons
- Spinal cord.
- In many places, noradrenaline is the excitatory chemical mediator, and in very few places, it causes inhibition. It is believed to be involved in dreams, arousal, and elevation of moods.
Dopamine: Dopamine is secreted by nerve endings in the following areas
- Basal ganglia
- Hypothalamus
- Limbic system
- Neocortex
- Retina
- Small, intensely fluorescent cells in sympathetic ganglia.
- Dopamine possesses inhibitory action. The prolactin inhibitory hormone secreted by the hypothalamus is considered to be dopamine.
Serotonin: Serotonin is otherwise known as 5-hydroxy tryptamine (5″HT). it is synthesized from tryptophan by hydroxylation and decarboxylation. Large amount of serotonin (90%) is found in enterochromaffin cells of Gl TsioL Small amount is found in platelets and the nervous system, it is secreted in the following structures:
- Hypothalamus
- Limbic system
- Cerebellum
- Dorsal raphe nucleus of midbrain
- Spinal cord
- Retina
- Gl tract
- Lungs
- Platelets.
- It is an inhibitory substance. It inhibits impulses of pain sensation in the posterior gray horn of the spinal cord. It is supposed to cause depression of mood and sleep.
- Serotonin causes vasoconstriction, platelet aggregation, and smooth muscle contraction. It also controls food intake.
Histamine: It is secreted in nerve endings of the hypothalamus, limbic cortex, and other parts of the cerebral cortex. It is also secreted by gastric mucosa and mast cells. Histamine is an excitatory neurotransmitter. It is believed to play an important role in arousal mechanism.
Gamma-Aminobutyric Acid (Gaba): GABA is an inhibitory neurotransmitter in synapses particularly in CNS. It is responsible for presynaptic inhibition. It is secreted by nerve endings in the following structures:
- Cerebral cortex
- Cerebellum
- Basal ganglia
- Spinal cord
- Retina.
- GABA causes synaptic inhibition by opening potassium channels and chloride channels. So, potassium comes out of synapse and chloride enters.
- This leads to hyperpolarization which is known as inhibitory postsynaptic potential (IPSP).
Substance P
- Substance P is a neuropeptide that acts as a neurotransmitter and as a neuromodulator. Substance P is a polypeptide with 11 amino acid residues.
- It belongs to a family of 3 related peptides called neurokinins or tachykinins. The other peptides of this family are neurokinin A and neurokinin B which are not well known like substance P.
- Substance P is secreted by the nerve endings (first-order neurons) of the pain pathway in spinal cord. It is also found in many peripheral nerves, and different parts of brain, particularly the hypothalamus, retina, and intestine.
- It mediates pain sensation. It is a potent vasodilator in CNS. It is responsible for the regulation of anxiety, stress, mood disorders, neurotoxicity, nausea, and vomiting.
Nitric Oxide
- Nitric oxide (NO) is a neurotransmitter in the CNS. It is also an important neurotransmitter in the neuromuscular junctions between the inhibitory motor fibers of the intrinsic nerve plexus and the smooth muscle fibers of the Gl tract.
- Nitric oxide acts as a mediator for the dilator effect of acetylcholine on small arteries. In the smooth muscle fibers of arterioles, nitric oxide activates the enzyme guanylyl cyclase, which in turn causes formation of cyclic guanosine monophosphate (cGMP) from GMP.
- The cGMP is a smooth muscle relaxant and it causes dilatation of arterioles. Thus, nitric oxide indirectly causes dilatation of arterioles.
- The peculiarity of nitric oxide is that it is neither produced by the neuronal cells nor stored in the vesicles. It is produced by non-neuronal cells like the endothelial cells of blood vessels. From the site of production, it diffuses into the neuronal and non-neuronal cells where it exerts its action.
Neuromodulators
- Neuromodulators Definition
- A neuromodulator is the chemical messenger which modifies and regulates activities that take place during synaptic transmission.
- These peptides do not propagate nerve impulses like neuromodulators
- Neuromodulators vs Neurotransmitters:
- The neuromoduiators are distinct from neurotransmitters. However, both terms are wrongly interchanged. Neurotransmitters propagate nerve impulses through synapses whereas neuromodulators modify and regulate the activities of synaptic transmission.
- Neurotransmitters are packed in small vesicles in axon terminals only. But neuromodulators are generally packed in large synaptic vesicles which are present in all parts of neurons like soma, dendrite, axon, and nerve endings. Many neurons have one conventional neurotransmitter and one or more neuromodulators.
- Few peptides like substance P act as neurotransmitters and neuromodulators.
- Actions of Neuromodulators: Neurotransmitters affect the excitability of other neurons or other tissues (like muscle fiber) by producing depolarization or hyperpolarization through the receptors of ionic channels. But neuromodulators have diverse actions such as:
- Regulation of synthesis, breakdown or reuptake of neurotransmitter
- Excitation or inhibition of membrane receptors by acting independently or together with the neurotransmitter
- Control of gene expression
- Regulation of local blood flow
- Promotion of synaptic formation
- Control of glial cell morphology
- Regulation of behavior.
- Chemistry of Neuromodulators: Generally, neuromodulators are peptides. So the neuromodulators are often referred as neuropeptides Almost all the peptides found in nervous tissues are neuromodulators.
- Types of Neuromodulators: Neuromodulators are classified into two types
- Non-opioid peptides
- Opioid peptides
- Non-Opioid Peptides: The non-opioid neuropeptides act by binding with G-protein coupled receptors. These neuropeptides are also called non-opioid neuromodulators. The non-opioid peptides are listed in Table.
- Opioid Peptides
- The peptides, which bind to opioid receptors are called opioid peptides. Opioid peptides are also called opioid neuropeptides or opioid neuromodulators.
- Opioid receptors are the membrane proteins located in nerve endings in the brain and Gl tract. Opioid receptors are of three types μ, κ, and δ. These proteins are called opioid receptors because of their affinity towards the opiate or morphine, which are derived from opium.
- Opium is the juice of white poppy (papaver somniferum). It is used as a narcotic to produce hallucinations and induce sleep. Opiate also induces sleep. Morphine is a powerful analgesic (pain reliever). Both opiate and morphine have high medicinal values but are highly addictive.
- These two substances act by binding with the receptor proteins (opioid receptors) for the natural neuropeptides. The natural neuropeptides are called endogenous opioid peptides.
- The endogenous opioid peptides have opiate-like activity and inhibit the neurons in the brain involved in pain sensation. Three types of opioid peptides are identified.
- Enkephalins
- Dynorphins
- Endorphins
- Enkephalins: Enkephalins are the natural opiate peptides recognized first in a pig’s brain. Derived from the precursor proenkephalin, these peptides are present in the nerve endings in many parts of the forebrain, substantia gelatinosa of the brainstem, spinal cord, and Gl tract. Two types of enkephalins are known, leucine enkephalin (YGGFL) and met-enkephalin (YGGFM).
- Dynorphins: Dynorphins are derived from prodynorphin. Dynorphins are found in the hypothalamus, posterior pituitary, and duodenum. Dynorphins are of two types, α and β dynorphins.
- Endorphins: Endorphins are large peptides derived from the precursor pro-opiomelanocortin. Endorphins are predominant in the diencephalic region particularly the hypothalamus and anterior and intermediate lobes of the pituitary gland. Three types of endorphins are recognized, α, β and γ endorphins.
Cotransmission And Cotransmitters
- Cotransmission is the release of many neurotransmitters from a single nerve terminal. Cotransmitters are the neurotransmitter substances that are released in addition to the primary transmitter at the nerve endings.
- For many years, it was believed that each neuron releases only one neurotransmitter substance from its terminals. Now it is known that some of the neurons release many neurotransmitter substances. It is also believed that the additional neurotransmitters, i.e. the cotransmitters modulate the effects of pHTtsuy neurotransmitters.
CCK= cholecystokinin.
VIP = vasoactive intestinal polypeptide.
CRH= corticotropin-releasing hormone.
GHRH = growth hormone releasing hormone.
GHRP = growth hormone releasing polypeptide.
TRH = thyrotropin-releasing hormone.
ANP= atrial natriuretic peptide.
BNP = brain natriuretic peptide.
CNP = C-type natriuretic peptide.
- Some of the primary neurotransmitters act as transmitters in other nerve endings.
- Examples of transmitters are:
- Calcitonin
- Dopamine
- Dvnorphin
- GABA
- Gene-related peptide
- Glutamate
- Glycine
- Neuropeptide Y
- Substance P
- VIP.
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