Previously we studied about the signal propagation in neurons and sensory signals. This week we will learn about the chemical messengers that transmit messages from nerve cells across the synapse to target cells which can be nerve cells, muscle cells or a glandular cells.
Neurotransmitters are the chemicals produced by the nerve cell particularly to transmit messages. There are three main classes of neurotransmitters: amino acids, amines and peptides. One of the exceptions to these chemical compositions is, however, acetylcholine, which is derived from acetyl CoA and choline. A molecule can only be called a neurotransmitter if it is synthesized and stored at a presynaptic neuron and released from a presynaptic axon terminal following the simulation and produce a response in post-synaptic cell.
It’s suggested that most neurons follow the Dale’s principle, i.e. a single neuron has only one neurotransmitter. However, many peptide containing neurotransmitters don’t follow this rule, they have co-transmitters, i.e. they possess more than one neurotransmitter which is released from the nerve terminal.
Acetylcholine (ACh) is a cholinergic neurotransmitter and is located at the neuromuscular junction and is therefore synthesized by the motor neurons in the spinal cord and the brain stem. It also participates in the functions of specific circuits in the peripheral and central nervous system. The synthesis of ACh requires an enzyme, choline acetyltransferase. There’s also a degenerative enzyme for ACh, acetylcholinesterase, which is synthesized mainly in cholinergic neurons, but also in some other neurons as well. The synthesis and degeneration of ACh are presented in detail in figure 1.
The catecholamine neurotransmitters, dopamine (DA), norepinephrine (NE), and epinephrine contain a chemical structure called catechol and they are amines, which gives them their collective name. They are in the part of the nervous system which controls mood, movement, attention and visceral function. In general, catecholamines are synthesized from tyrosine, hence all catecholamine neurons contain the enzyme tyrosine hydroxylase (TH), which catalyzes the first step of the synthesis. Detailed steps of this synthesis are presented in figure 2.
Serotonergic neurons use serotonin as a neurotransmitter. This neurotransmitter is observed to regulate mood, emotional behavior, and sleep. Serotonin is synthesized from tryptophan, which we get mainly through the blood, by two specified enzymes. The source of the tryptophan in blood is our diet, e.g. dairy, meat, grains and chocolate.
Amino acidergic neurons use amino acids, glutamate (Glu), glycine (Gly), and gamma-aminobutyric acid (GABA), as neurotransmitters. Glutamate and glycine are synthesized from glucose and other precursor molecules by common enzymes which are found in many parts in the body. GABA in turn, is synthesized from glutamate by glutamic acid decarboxylase (GAD). The neurons which use GABA, GABAergic neurons, are scattered widely in the brain and they are the main source of synaptic inhibition in the nervous system.
Other molecules, such as adenosine triphosphate (ATP), a key molecule in cellular metabolism, can also be counted into neurotransmitters in certain situations, as it has functions as a messenger between the neurons. ATP can occur as a co-transmitter e.g. with GABA or ACh in various specified neurons.
Lastly, it is relevant to point out that many of the chemicals and molecules we tend to call neurotransmitters can also be present in high concentrations in non-neural parts of the human body, having entirely different functions compared to what is their purpose in the neural systems.
Neurotransmitters control the passage of chemicals through transmitter-gated channels. They can be described as tiny machines that are formed by protein subunits. For example, the nicotinic ACh receptor is built of five subunits. Each subunit forms one side of a pore that requires the attachment of two ACh-molecules to open. There are two different types of transmitter-gated channels: glutamate– and GABA-glycine-gated channels. The structure of ACh-receptor is presented in figure 3.
Amino acid-gated channels are abounding in the central nervous system mediating fast synaptic transmission. They differentiate from another by their pharmacology, kinetics, selectivity and conductance. These all are results of the molecular structures of the channels. The pharmacology of channels defines which neurotransmitters bind to them and how drugs affect them. The kinetics describe the duration of the effect of neurotransmitters depending on the binding process. Selectivity refers to the exciting or inhibiting effect that the binding produces. The magnitude of the effects of a channel can be determined by conductance.
Glutamate-gated channels can be subcategorized to AMPA-, NMDA– and kainate-gated channels which are named after their agonists. AMPA- and NMDA-gated channels mediate most of the fast and excitatory transmission in the brain. AMPA-gated channels are permeable to natrium and potassium ions. When they are activated during normal membrane potentials, an excess number of cations are allowed inside the cell and it depolarizes rapidly. NMDA-gated channels are similar except for their permeability to calcium ions and voltage-dependent inward current. Calcium ions are essential to multiple cell functions; presynaptic neurotransmitter release, enzyme activation, channel opening and gene expression. The functions of kainate-gated channels are not entirely understood.
GABA- and glycine-gated channels are inhibitory and transfer chloride ions. Multiple drugs can bind to GABA-gated channels and affect their functions if bound with GABA-molecules. For example, benzodiazepines increase the frequency of channel openings and barbiturates the duration of an opening. Furthermore, ethanol enhances inhibition in some GABA-gated channels but not others. There are additionally neurosteroids which act on GABA-gated channels either enhancing or suppressing inhibitory functions. The functions of naturally occurring neurosteroids and many other chemicals are still unknown.
G-Protein Coupled Receptors and Effectors
G-proteins are the common link in most signaling pathways that originates with a neurotransmitter receptor and end with effector proteins. G protein stands for guanosine triphosphate binding protein, which consists a family of about 20 types. Some types of G-proteins can be activated by several receptors.
The G-protein-coupled receptors contain various subtypes. A remarkable number of G-protein-coupled receptors are simple variations of a common structure, consisting of a single polypeptide that contains seven-membrane-spanning alpha helices. Two extracellular loops of the polypeptide form the transmitter binding sites.
Structural variation in this region determines the type of neurotransmitter agonists or antagonists that bind to the receptor. There is a possibility that even two of the extracellular loops of the polypeptide form can bind to and activate G-proteins. The structural variation in this place determine which G-proteins and effector systems will be activated in response to transmitter binding. The human genome has genes coding for about 800 different G-protein coupled receptors and they are organized into five major families with similar structures. G-protein-coupled receptors are important in all the body’s cell types, not just neurons.
G-proteins exert their effects by binding to either type of effector proteins: G-protein–gated ion channels and G-protein-activated enzymes. As the effects do not involve any other chemical intermediaries, the first route is sometimes called the shortcut pathway.
There are numerous neurotransmitters that use the shortcut pathway, from receptor to G-protein to ion channel. These pathways are the fastest of the G-protein-coupled-systems, having responses that starts within 30-100 msec of neurotransmitter binding. There are not quite as fast as transmitter-gated channel described above but still this faster than other transmission channels. The shortcut pathway is also very localized compared with other effector systems. This only affects the nearby channels as G-protein diffuses within the membrane. As all the action in the shortcut pathway occurs within the membrane, it is also known as membrane-delimited pathway.
Additionally, G-proteins exert their effects by directly activating certain enzymes and cause second messenger cascades. Sometimes an elaborate series of biochemical reactors are triggered due to the activation of these enzymes. This cascade often ends in the activation of other “downstream” enzymes that alter neuronal function. There are several second messengers between the first and last enzyme. The whole process that couples the neurotransmitter via multiple steps is called a second messenger cascade.
Function of Signal Cascades: Signal cascading provides signal amplification, the activation of one G-protein coupled receptor can lead to activation of not one but many ion channels. Signal amplification can and occurs at several places in the cascade. The use of small messengers that can diffuse quickly (such as cAMP) also allows signaling at a distance, over a wide stretch of cell membrane. Signal cascades also provide many sites for further regulation as well as interaction between cascades. Also signal cascades can generate very long-lasting chemical changes in cells, which may form the basis for, among other things, a lifetime of memories.