This week we focused on neurotransmitters. We learned about the general chemistry and function of neurotransmitters and examined specific types of neurotransmitters in detail. In order for a chemical in the brain to be considered a neurotransmitter, it must be synthesized and stored in the presynaptic neuron, as well as released when triggered. In addition, a response to the release of the chemical from the presynaptic cell must occur in the postsynaptic neuron. Research has concluded that most neurotransmitters are amino acids, amines (derived from amino acids), or peptides (also consisting of amino acids). Neurons are classified into categories based on which kind of neurotransmitter they release (Dale’s Law). Many chemicals that fill the requirements of being a neurotransmitter are also present in other parts of the body.
We explored two different ways of generating electrical and biochemical signals in the postsynaptic neuron; transmitter-gated ion channels and G-protein coupled receptors. Transmitter-gated ion channels are faster at transmitting a signal in the postsynaptic neuron than G-protein coupled receptors. Most of these channels contain four hydrophobic segments that spread throughout the membrane with subunits that contain different receptors for different neurotransmitters. The differences between the structures of the channels are what determine which ions and transmitters flow through them.
Amino acid gated channels are responsible for most of the fast synaptic transmissions. The molecular structure of the channel is an indicator of the pharmacology, kinetics, selectivity, and conductance of channels. AMPA, NMDA, and kainate are all glutamate-gated ion channels. AMPA and NMDA-gated channels are responsible for much of the excitatory synaptic transmission in the CNS. They work together, but unlike AMPA, NMDA-gated channels are permeable to calcium ions and are also voltage-dependent as well as transmitter-gated. GABA-gated and glycine-gated channels are selectively permeable to chloride ions. GABA is responsible for much of the synaptic inhibition in the CNS, while glycine is responsible for most of the rest.
Transmission at G-protein receptors involves the binding of a neurotransmitter to a receptor protein, subsequent activation of G-proteins, and resulting activation of other effectors. Many G-protein coupled receptors have seven alpha helices that penetrate the membrane with a binding site for G-proteins on the inside of the membrane. G-proteins have three subunits, and in the inactive stage, a GDP molecule is connected to one of the subunits. When a receptor with a neurotransmitter binds to a G-protein, it releases the GDP molecule and gets a GTP from the cytosol. From then the G-protein is free to activate other effector proteins. While G-protein coupled transmission involves more steps and is more complex than fast synaptic transmission, this kind of transmission can cause an elaborate network of biochemical reactions, called a signal cascade. Therefore the signal may be amplified, and cause long-lasting changes in cells. Neurotransmitters can activate many subtypes of receptors; this phenomenon is known as divergence, and it can happen at any point of the signal cascade. Many different transmitters can also come together to trigger the same effector; called convergence. These paths of signals can be thought of as a network of information that is amplified and sent along to different neurons.
Next we will discuss two different kinds of neurons in more detail.
Acetylcholine (ACh) is a neurotransmitter used in various systems of the body. It is commonly known as the neurotransmitter that binds to nicotinic ACh receptors in neuromuscular junctions, in which nicotine is an agonist. Another type of receptor is the muscarinic ACh receptor in the heart, in which muscarine is an agonist. Most neurotransmitters are either amino acids, amines derived from amino acids, or peptides made up of amino acids. These types of neurotransmitters are common because they are considered the basic chemicals of life. On the other hand, ACh is derived from acetyl CoA, which is a product of cellular respiration in the mitochondria, and choline used for fat metabolism. CoA and choline are also abundant in human cells.
Cholinergic neurons have an interesting mechanism for creating ACh in the synapse. The main enzyme required for making ACh is choline acetyltransferase (ChAT). ChAT is transported from the soma to the neuron terminals. It combines choline and acetyl CoA to create ACh. ACh is subsequently packed into vesicles by transporters. The presynaptic terminal’s source of choline comes from the extracellular space. A cotransporter is used that brings in Na+ and choline into the presynaptic terminal. The transport of choline into the presynaptic terminal is considered the rate-limiting step in the formation of ACh.
Another extremely important enzyme for cholinergic neurons is acetylcholinesterase (AChE). AChE performs the reverse reaction of ChAT by breaking ACh into choline and acetylcholine in the synaptic cleft. AChE has one of the fastest catalytic rates of all enzymes. AChE is essential to regulating the excitation of cholinergic neurons, which is a reason why it is the target of attack for many nerve agents. Inhibition of AChE results in ACh overload producing constant nerve stimulation. Consequently, nerves become fatigued which can lead to respiratory paralysis if left untreated. In addition, blood pressure and heart rate drop significantly.
This August, Russian opposition activist, Alexi Navalny, was poisoned in Russia with a deadly chemical nerve agent inhibiting AChE called Novichok (Simmons, 2020). He was transported to Germany, put on a respiratory ventilator, and survived. Novichok was developed by the Soviet Union. Novichok causes sudden cardiac arrest and respiratory paralysis. One of the drugs used to treat Mr. Navalny was atropine. In class we learned that atropine is an antagonist to muscarinic ACh receptors. Therefore, in the absence of functioning AChE, atropine can act as a regulatory mechanism to reduce the firing of neurons by keeping the ion channels with muscarinic ACh receptors closed. Atropine isn’t a cure but a quick solution to counteract the deadly, sudden effects of Novichok. Atropine is derived from “deadly nightshade,” a plant that in normal circumstances is toxic. However, in Mr. Navalny’s case, deadly nightshade saved his life (Simmons, 2020).
Amino acidergic neurons
There are many amino acids that serve as a neurotransmitter, like glutamate, glycine and gamma-aminobutyric acid (GABA) from which only GABA is uniquely used as a neurotransmitter in the brain and spinal cord. Therefore, we mainly focus on GABA, even though many aspects of its working principles can also be applied to other neurotransmitter amino acids. GABA is a four-carbon non-protein amino acid that is synthesized in large quantities only by GABAergic neurons.
GABA is synthesized from glutamate through decarboxylation via glutamate decarboxylase enzyme. The release of GABA is a similar mechanism as with other neurotransmitters. When a nerve impulse reaches axon terminal, the vesicles containing GABA degranulates and GABA is released into the synaptic cleft where it reaches the postsynaptic neuron. There are two types of GABA receptors where the molecule can bind to, GABAA and GABAB. GABAA is a chloride ion channel coupled receptor which causes an increase in the chloride ion influx into the neuron. GABAB is a G-protein coupled receptor that causes an increased opening of potassium channels transmitted by second messengers. They also decrease the activity of adenyl cyclase enzyme and calcium channels. All of the effects mentioned above increase depolarization of the neurons, therefore increasing the threshold potential. Hence, GABA is responsible for decreasing neuronal excitability and participating in multiple inhibitory nervous signals.
Since GABAergic neurons are inhibitory, they have numerous effects in the body such as relieving anxiety and stress in addition to controlling blood pressure and heart rate, just to name a few. Studies have also found that altered GABA signaling is associated with different brain diseases like ADHD, depression, anxiety and epilepsy. For instance, the latter is associated with ionic changes in postsynaptic GABAA receptors which causes decreased expression of these receptors. GABA mimetic drugs can therefore be used to treat epilepsy patients. (The Human Memory, 2020)
GABA, The Human Memory, 2020. Available (accessed on 11.10.20): https://human-memory.net/gaba/
Simmons, Ann. “What Is Novichok, the Nerve Agent Used to Poison Alexei Navalny?” The Wall Street Journal, Dow Jones & Company, 17 Sept. 2020, www.wsj.com/articles/what-is-novichok-the-nerve-agent-used-to-poison-alexei-navalny-11599072960.