Chemical synapses

Structure

A chemical synapse consists of several key components:

• The presynaptic terminal: Also known as the synaptic knob, it is located along an axon or at its terminal end. It is densely packed with mitochondria and contains synaptic vesicles—membrane-bound spheres that store neurotransmitters. This terminal also houses voltage-gated Ca²⁺ channels.
• Neurotransmitters: These chemical molecules act as messengers that transmit information between the two cells involved in the chemical synapse. They can be categorized into four categories based on their chemical structure:
  1. Monoamines (dopamine, epinephrine, norepinephrine, histamine, and serotonin)
  2. Amino acids (glutamate, GABA and glycine);
  3. Neuropeptides (substance P, neuropeptide Y, endorphins, enkephalins, vasopressin and oxytocin);
  4. Others (acetylcholine, nitric oxide, endocannabinoids)
• The synaptic cleft: This is a narrow gap, approximately 20-30 nm wide, between the presynaptic and postsynaptic membranes. It allows neurotransmitters to diffuse across to the postsynaptic neuron, facilitating precise regulation of neurotransmitter concentration.
• The postsynaptic membrane: It contains protein receptors that bind to neurotransmitters released from the presynaptic terminal, functioning according to a key-lock mechanism. Depending on how they induce their effects, these receptors can be:
  1. Ionotropic receptors: Ligand-gated channels that directly open ion channels upon neurotransmitter binding.
  2. Metabotropic receptors: G-protein-coupled receptors that initiate signaling cascades, leading to the activation of ion channels and inducing intracellular metabolic changes.

Function

When an action potential reaches the axon terminal, it activates voltage-gated Ca²⁺ channels, resulting in a significant influx of Ca²⁺ ions into the nerve endings. This increase in Ca²⁺ concentration at the presynaptic terminal triggers the release of neurotransmitters from vesicles containing these chemical messengers. The amount of neurotransmitter released is directly proportional to the Ca²⁺ concentration.

The exocytotic release of neurotransmitters depends on the interaction and conformational changes of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins with Ca²⁺ sensor proteins. Vesicular SNARE proteins form a complex with plasma membrane SNARE proteins at active zones of the release sites, enabling the fusion of the vesicle with the membrane and the subsequent diffusion of neurotransmitters into the synaptic cleft. This process, known as "docking," prepares the vesicles for rapid fusion upon Ca²⁺ influx, a step referred to as "priming."

After releasing their contents, the vesicle membranes are retrieved through a clathrin-mediated process, while the neurotransmitters bind to their corresponding receptors on the postsynaptic membrane. Any remaining or unbound neurotransmitters are either reabsorbed into the presynaptic terminal or degraded by enzymes. The emptied vesicles, having undergone recycling, are refilled with neurotransmitters through active transport mechanisms. This refilling involves the use of H⁺ ATPase to pump protons, creating an electrochemical gradient that facilitates the exchange of neurotransmitter molecules for protons.
An alternative model of vesicle release is the “kiss-and-run fusion,” where neurotransmitter-containing vesicles dock and transiently fuse with the presynaptic membrane without fully collapsing into it. This mechanism allows for faster vesicle recycling.

Each vesicle can carry between 2,000 and 10,000 neurotransmitter molecules, and the presynaptic terminal contains enough vesicles to support up to 10,000 action potentials.

Neurotransmitter receptors

Neurotransmitters bind to receptors on the postsynaptic membrane in a manner similar to a key fitting into a lock. These receptors have two primary components: an external binding site that projects into the synaptic cleft and an internal structural element that spans the membrane.

There are two main types of receptors:

• Ionotropic receptors: These are ligand-gated ion channels that open directly in response to neurotransmitter binding, enabling rapid signaling. Examples include AMPA and NMDA receptors for the neurotransmitter glutamate, as well as GABA_A receptors.
• Metabotropic receptors: These receptors trigger a cascade of intracellular events, leading to metabolic changes that result in a slower and more sustained response. Examples include mGluRs for glutamate and GABA_B​ receptors. Metabotropic signaling involves several components:
  
  • The transmembrane receptor protein on the extracellular surface binds the neurotransmitter, acting as the "first messenger."
  • This binding activates the associated G protein, a GTPase, on the intracellular side.
  • The G protein then activates an effector protein, typically an enzyme that catalyzes the production of a "second messenger," which serves as an intracellular mediator of the signal.

Second messengers can induce widespread metabolic changes within the cell and may also lead to the opening or closing of ion channels.

Excitatory versus inhibitory synapses

Chemical synapses can be classified as excitatory or inhibitory based on their effects on the postsynaptic cell. Excitatory synapses depolarize the postsynaptic membrane by opening Ca²⁺ or Na⁺ ion channels, increasing the intracellular concentration of cations. This depolarization makes the generation of an action potential more likely. In contrast, inhibitory synapses hyperpolarize the postsynaptic membrane by opening Cl⁻ or K⁺ ion channels, reducing the likelihood of an action potential by making the membrane potential more negative.

The nature of each synapse—whether excitatory or inhibitory—is determined by the neurotransmitter released from the presynaptic terminal and the specific receptors present on the postsynaptic membrane. Each neuron synthesizes a particular neurotransmitter for use at its synapses, leading to classifications such as glutamatergic, GABAergic, or dopaminergic neurons, which release glutamate, GABA, and dopamine, respectively.

The effect of a neurotransmitter on the postsynaptic cell ultimately depends on the type of receptors it activates. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), as its receptors depolarize the postsynaptic membrane upon binding. Conversely, GABA is the main inhibitory neurotransmitter in the CNS, causing hyperpolarization through its receptor activation.

Other neurotransmitters, such as dopamine, can be either excitatory or inhibitory depending on the types of receptors expressed on the postsynaptic membrane. For example, dopamine has an excitatory effect through D1 receptors and an inhibitory effect through D2 receptors.

Chemical versus electrical synapses

Chemical and electrical synapses differ in several key aspects. Chemical synapses use neurotransmitters to transmit signals across the synaptic cleft, whereas electrical synapses transmit signals directly through ion currents via gap junctions. In humans, chemical synapses are predominant because they facilitate the complex processing required by the nervous system.

One major advantage of chemical synapses is their ability to ensure one-way transmission of nerve impulses: neurotransmitters are released from the presynaptic membrane and bind to receptors on the postsynaptic membrane, preventing reverse signaling. In contrast, electrical synapses allow bidirectional signal transmission, which can be less effective for controlled signaling.

Additionally, chemical synapses offer high specificity due to the wide variety of neurotransmitters and their corresponding receptors, enabling a diverse range of neuronal responses. In contrast, electrical synapses provide a more straightforward mode of transmission with limited modulation, which is less suitable for complex processing.

However, because neurotransmitter release, diffusion, and receptor binding take time, chemical synapses transmit signals more slowly than electrical synapses, which enable nearly instantaneous transmission through direct ionic flow.