Table of Contents
Introduction to neurotransmitters and receptors
Neurotransmitters are the chemical substances that bring about the transmission of information at the chemical synapses. Neurons make connections with each other in the form of chemical junctions which are termed chemical synapses. At chemical synapses, neurotransmitters are released from the presynaptic membrane into the synaptic cleft. These neurotransmitters bind at the receptors which are located at the postsynaptic membrane and activate specific channels. This activation of channels leads to the transmission of information between the neurons. Receptors are the specific structures that bind specific chemical substances termed ligands. There are several types of receptors located at different locations inside the body. There are also several neurotransmitters involved in synaptic transmission in the central nervous system and peripheral nervous system. Some neurotransmitters are specific for CNS only while some work in both CNS and PNS.
The chemicals performing the job of neurotransmitters may open an ion channel or stimulate a G protein-coupled receptor in the postsynaptic membrane. The ion channels may be cationic or anionic. If a neurotransmitter opens cationic channels and allows sodium ions to enter the cell, it is called an excitatory neurotransmitter as the influx of sodium depolarizes the cell. However, if a neurotransmitter opens potassium ion channels, it will allow the potassium to leak out of the cell as a result the intracellular membrane potential will fall and the cell is hyperpolarized so it will act as an inhibitory neurotransmitter.
If a neurotransmitter opens anionic channels it will allow the negatively charged ions to move inside the cell as a result inside of the cell becomes more and more negative and this will hyperpolarize the cell, acting as an inhibitory neurotransmitter. Neurotransmitters may produce the response via G protein-coupled receptors. In this case, their response depends upon whether they activate a signaling pathway or inhibit a signaling pathway. The same neurotransmitter may act as an excitatory neurotransmitter at one location and as an inhibitory transmitter at another location depending upon the receptors. There are more than 50 chemical substances that are recognized as neurotransmitters performing the role of synaptic transmissions.
Classification of Neurotransmitters
They are broadly classified into two groups, one group comprises the small molecules which are rapidly acting; the other group is made up of a large number of peptides that have large molecular sizes and act slowly. These small, rapidly acting neurotransmitters are involved in the acute responses of the nervous system such as the transmission of sensory signals from the body to the CNS and the transmission of motor signals back from the CNS to the body.
However, the slow-acting neuropeptides cause prolonged responses such as long-term changes in the number of receptors, long-term opening or closing of certain ion channels at certain body locations, long term changes in the number & size of synapsis.
Small, rapidly acting neurotransmitters
Small rapidly acting neurotransmitters are the most important neurotransmitters in acute body responses. They are usually synthesized into the cytosol of the axons and then transmitted into the transmitter vesicles via active transport. When the cell terminal is depolarized by the action potential, calcium channels at the cell terminals open and there is an increase in the calcium ion concentration in the cytosol, and v-SNARE proteins react with t-SNARE proteins; their interaction results in the docking of transmitter vesicles at the nerve terminal and their release into the synaptic cleft. This action is quite rapid occurring in a millisecond or less. The neurotransmitter acts on the receptors located at the post-synaptic membrane and stimulates either sodium channels to increase sodium conductance leading to excitation or it causes an increase in the potassium or chloride conductance which results in the inhibition of the next neuron. This action is also quite rapid occurring within a millisecond or less.
The remaining transmitter substance located in the synaptic cleft is either degraded or it is again transferred into the cytosol of the cell by the reuptake mechanism. The vesicles which are docked at the terminal membrane are recycled and reused. They are pinched off from the terminal membrane and are converted into vesicles again. They contain the necessary transport proteins to concentrate the transmitter substances in them. The most important small, rapidly acting neurotransmitters include acetylcholine, norepinephrine, dopamine, glycine, gamma-aminobutyric acid (GABA), and nitric oxide. Let’s discuss them individually.
Acetylcholine is a common neurotransmitter in both the central nervous system as well as the peripheral nervous system. It is released from the terminals of the large pyramidal cells from the motor cortex. It is also released by different types of neurons in the basil ganglia as well as somatic motor neurons that supply the skeletal muscles. Acetylcholine is the primary neurotransmitter at the terminal of the preganglionic fibers in the autonomic nervous system. The postganglionic neurons of the parasympathetic nervous system and some neurons of the sympathetic nervous system such as nerves supplying the thermoregulator sweat glands and the vasodilator fibers in the skeletal muscles also use acetylcholine as neurotransmitters. It is mainly an excitatory neurotransmitter; however, it also acts as an inhibitory neurotransmitter at some parasympathetic nerve endings such as the inhibition of cardiac muscles by the vagus nerve.
Norepinephrine is the neurotransmitter involved in synaptic transmission in the both central nervous system as well as the peripheral nervous system. It acts as an excitatory transmitter as well as an inhibitory transmitter depending upon the receptors. Norepinephrine released from the neurons in the pones controls the overall wakefulness and excitability of the entire brain. It is also a principal neurotransmitter at the postganglionic sympathetic terminals except the fibers supplying the thermoregulatory sweat glands and vasodilator fibers in the skeletal muscles which release acetylcholine.
Dopamine is the principal neurotransmitter that plays its role in neuronal transmission primarily in the central nervous system. It acts mainly as an inhibitory neurotransmitter.
In the central nervous system, there are three tracks that involve dopamine as a primary neurotransmitter. These tracts include the nigrostriatal tract, mesolimbic-mesocortical tract, and tuberoinfundibular tract. Dopamine in the nigrostriatal tract controls muscle movements. Any disturbance in this tract can cause parkinsonism or dyskinesia. In the mesolimbic-mesocortical system, dopamine controls cognitive functions and reinforcement. An increase in dopamine in this tract causes psychoses. Dopamine in the tuberoinfundibular tract controls prolactin and growth hormone release.
Glycine is the inhibitory neurotransmitter in the central nervous system involved in the processing of sensory and motor information concerning vision, audition, and movement.
Gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the central nervous system. It inhibits the neurons’ ability to receive, create and send chemical messages in the form of nerve impulses. It is well known for its calming effect and is thought to play a role in controlling nerve cell hyperactivity due to fear or anxiety. Many drugs work by promoting GABA activity in the brain cells to relieve anxiety and stress. GABA plays its inhibitory role by opening the chloride ion channels in the postsynaptic membrane.
Glutamate is an excitatory neurotransmitter made by glial cells in your brain. It is the most abundant excitatory neurotransmitter in brain circuits and controls the excitability of the cortex. It is also required to synthesize GABA.
Serotonin is an excitatory neurotransmitter in CNS and enteric nervous system. It controls mood and behavior and is useful in depression & anxiety. About 90% of body serotonin is found in the GIT tract while 10% is in the brain.
Nitric oxide is a neurotransmitter in the nervous system that is considered to be involved in long-term behavior and memory. It is different from the other short-acting neurotransmitters due to its way of synthesis and release. It is not stored in the vesicles instead it is synthesized at the moment when required from arginine by the action of enzyme NO synthase. It diffuses into the postsynaptic neurons and changes the intracellular metabolic functions that alter neuronal excitability.
Neuropeptides have a different mechanism of synthesis and act differently than short-acting neurotransmitters. They are not synthesized in the axonal cytoplasm (axoplasm)l; instead, they are synthesized in the ribosomes and then processed into the endoplasmic reticulum and Golgi apparatus. Inside the Golgi apparatus, they are packed into the small transmitter vesicles and released into the cytoplasm. From the cytoplasm, they are transferred into the axonal terminals via axonal streaming and then released into the synaptic cleft upon stimulation. The vesicles are degraded and aren’t recycled in this case. Due to the tedious method of synthesis, only a small amount of neuropeptides is released. They are more potent than short-acting neurotransmitters and cause prolonged effects. They produce several effects such as prolonged closer of calcium channels, changes in the metabolic activities of cells, changes in gene expression, and alteration in the number of excitatory or inhibitory receptors. Their effects may last for days, weeks, or even years. Some common neuropeptides include:
- Thyrotropin-releasing hormone
- Substance P
- Bradykinin etc.
Receptors are the body structures that detect internal or external stimuli. Receptors can be classified into 5 basic types depending on the stimuli they sense. These types include:
- Mechano receptors
- Electromagnetic receptors
- Chemical receptors
Each of these receptors is specialized to sense the specific modality of sensation. A common question may arise here: how do these specific receptors detect different types of stimuli?
The answer to this question is they have differential sensitivities for different types of stimuli. These specific receptors are more responsive to one kind of stimuli than the other which helps them to detect a wide range of stimuli. For example, the rods and cones in the eye are sensitive to light but they are almost sensitive to heat, cold or pressure, or chemical changes. Similarly, osmoreceptors in the supraoptic nucleus of the hypothalamus detect the osmolality of the body fluids but cannot respond to sound or light. Nociceptors are pain sensitive and are stimulated by pain or any damaging stimuli but cannot be stimulated by light or sound waves.
Let’s discuss the individual receptor types:
Mechanoreceptors detect mechanical stimuli such as touch, pressure, vibration, etc.
Mechanical receptors include several types of the receptor such as:
- Free nerve endings
- Meissner’s corpuscles
- Merkels disc
- Hair end organs
- Ruffini’s endings
- Pacinian corpuscles
Free nerve endings are present everywhere in the skin and many other tissues. They mainly detect touch and pressure sensations: for example, light contact on the surface of the cornea is sensed as touch and pressure because the surface of the cornea has only free nerve endings.
Meissner’s corpuscles are encapsulated nerve endings of large myelinated sensory nerve fibers. They are mainly present in the non-hairy parts of the skin such as fingertips, lips and many other areas where the person’s ability to recognize spatial locations of touch sensation are highly developed. They are also sensitive to the movement of projects over the surface of the skin and low-frequency vibration.
Fingertips and other areas of the body also contain expanded tip tactile receptors such as Merkel’s disc. They are also present in the hairy parts of the skin where the number of Meissner’s corpuscles is almost zero. These receptors transmit initially a strong signal but they adapt gradually and then transmit a weak signal that adapts much more slowly. Therefore they transmit a steady level of signals for a prolonged duration that allows oneself to sense the continuous touch stimuli of something against the skin.
Hair end organs are receptors that detect the slight movement of hair on the body. These receptors mainly detect the initial contact of an object with the body and movement of the object against the surface of the body but they adapt readily and then transmit very little or no signals.
Ruffini’s endings are present in the deep layers of skin and deep tissues. They detect the deformation of tissues due to continuous pressure, touch as well as joint rotation.
Pacinian corpuscles are present under the skin and deep in facial tissues. They are stimulated by local compressional forces and but they adapt very rapidly.
Thermoreceptors are free nerve endings distributed onto the skin that detect hot and cold stimuli. Their relative distribution varies in different parts of the body. Usually, cold receptors are in greater abundance compared to warmth receptors. However, if the stimuli reach the damaging range to the body tissues the nociceptors also become active.
Nociceptors are the pain receptors in the skin and detect noxious stimuli. They enable one to detect tissue damage and resort to the necessary measures. They are free nerve endings distributed in the skin, muscle joints, as well as internal viscera.
Electromagnetic receptors detect electromagnetic waves such as rods and cons inside the eyes. These specialized visual cells, rods, and cons in the eyes detect the visual spectrum of the light rays.
Chemical receptors respond to the concentration of different chemicals in body fluids such as chemoreceptors located in the supraoptic nuclei of the hypothalamus, receptors in the islets of the pancreas, taste buds, olfactory receptors, etc.
Neurotransmitters are the chemical substances that transmit messages at the chemical synapses. Neurotransmitters may act through channel-linked receptors or through G protein-coupled receptors.
They are broadly classified into small, rapidly acting neurotransmitters and long-acting neuropeptides.
Short, rapidly acting neurotransmitters are synthesized in the cytosol of axons and are stored in vesicles at the neuronal endings. Upon activation, these vesicles are rapidly released into the synaptic cleft, bind to postsynaptic receptors, and elicit a rapid response. Due to the fast onset of action, they are dominant in acute responses. The most common small, rapidly acting neurotransmitter include acetylcholine, norepinephrine, dopamine, glycine, GABA, glutamate, serotonin, nitric oxide, etc.
Long-acting neuropeptides are synthesized on ribosomes and then processed by the Golgi apparatus. They are slowly released and produce prolonged responses such as prolonged activation of receptors, change in the number of membrane receptors, alteration in gene expression, prolonged closure of calcium ion channels, etc. The most common neuropeptides include enkephalins, endorphins, thyrotropin-releasing hormone, somatostatin, prolactin, gastrin, substance P, bradykinin, etc.
Receptors are specialized body structures that detect several types of internal or external stimuli such as pain, heat, cold, touch, pressure, light, etc.
Sensory receptors include mechanoreceptors which detect mechanical stimuli such as touch, pressure, and vibration, thermal receptors which detect hot and cold stimuli, nociceptors which detect pain, electromagnetic receptors which detect light rays and chemoreceptors which detect different chemical substances in the body.
Sheffler ZM, Reddy V, Pillarisetty LS. Physiology, Neurotransmitters. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539894/