Chemical Synaptic Signalling Study Notes

Overview of Chemical Synaptic Signalling

Chemical synaptic signalling is a crucial form of intercellular communication that involves the transmission of signals between neurons through the release and reception of neurotransmitters. Key components of this process include:

  1. Chemical Signalling from Neurons: Neurons communicate via neurotransmitters, which are chemical messengers released into the synaptic cleft (the gap between the pre-synaptic and post-synaptic membranes).

  2. Regulation of Transmitter Release: The Role of Ca²⁺: Calcium ions (Ca²⁺) play a pivotal role in neurotransmitter release. The influx of Ca²⁺ into the pre-synaptic terminal triggers the release of neurotransmitters from synaptic vesicles.

  3. Vesicle Recycling: Following neurotransmitter release, vesicles are recycled for reuse, ensuring a sustainable supply of neurotransmitters for future signalling events.

  4. Post-Synaptic Fast and Slow Responses: The binding of neurotransmitters to receptors on the post-synaptic membrane can produce both rapid (fast) and gradual (slow) responses in the target neuron or cell.

  5. Post-Synaptic Voltage Responses: Changes in the voltage of the post-synaptic membrane can lead to excitatory or inhibitory effects, affecting neuronal excitability and signalling.

  6. Terminating the Signalling: The action of neurotransmitters must be terminated to reset the synapse for future signalling, which can occur through various mechanisms.

Classification of Chemical Signalling

Types of Chemical Signalling: Synaptic vs Non-Synaptic

  • Synaptic Chemical Signalling:

    • Usage: Exclusive to neurons.
    • Chemical Type: Neurotransmitters.
    • Distance: Typically short (affects adjacent cells).

  • Non-Synaptic Chemical Signalling:

    • Usage: Utilized by both neurons and non-neuronal cells.
    • Chemical Type: Hormonal and local chemical mediators (such as paracrine and autocrine signals).
    • Distance: Varied; long-distance (hormonal) or very short distance (autocrine).

Types of Synapses

  1. Discrete Synapses: Target specific adjacent postsynaptic cells, allowing precise communication.
  2. Diffuse Synapses: Involve the release of neurotransmitters that can affect a broader area or multiple cells.

Structure of the Synapse

Key Components

  1. Synaptic Cleft: A space approximately 20 nm wide located between the pre- and post-synaptic membranes.
  2. Pre-synaptic Terminal (or Varicosity): The site of neurotransmitter release, containing synaptic vesicles filled with neurotransmitters.
  3. Post-Synaptic Density: The area of the post-synaptic membrane containing receptors for neurotransmitters.
  4. Linking Proteins: Two significant proteins that facilitate synaptic transmission:
    • Neuroligin: Found on the post-synaptic membrane.
    • Neurexin: Located on the pre-synaptic membrane.
      These proteins interact across the synaptic cleft, enabling efficient synaptic signalling.

Chemical Transmission

Criteria for Chemical Transmission

To qualify as a true chemical transmission, the following criteria must be met:

  1. Synthesis of Neurotransmitter: Neurotransmitters must be synthesized in the presynaptic nerve terminal or cell body.
  2. Storage: They are stored in secretory vesicles until needed for release.
  3. Regulated Release: Neurotransmitters are released into the synaptic cleft in a regulated manner.
  4. Receptor Binding: The post-synaptic membrane must have specific receptors to bind the released neurotransmitters (except for gases like nitric oxide).
  5. Termination Mechanism: There must exist mechanisms to terminate the action of the neurotransmitter, ensuring precise communication.

Classes of Neurotransmitters

  • Non-peptide Neurotransmitters: Typically small molecules such as amino acids, monoamines, etc.
  • Peptide Neurotransmitters: These are larger molecules, formed from longer chains of amino acids.

Vesicularization of Neurotransmitters

Advantages of Vesicles

The use of vesicles for neurotransmitter storage provides several benefits:

  1. Concentration: Vesicles can contain between 5000 to 10,000 molecules of neurotransmitter, enhancing the likelihood of successful signal transmission across the synaptic cleft.
  2. Protection from Degradation: Vesicles protect neurotransmitters from being degraded by enzymes in the cytoplasm.
  3. Controlled Release: Neurotransmitter release can be finely controlled, ensuring that it is utilized specifically for signalling rather than being released indiscriminately.

Role of Ca²⁺ in Neurotransmitter Release

Vesicle fusion with the pre-synaptic membrane is triggered by the influx of Ca²⁺ ions. The entry of Ca²⁺ primarily occurs at specialized regions called Active Zones.

  1. Calcium Concentration: Normally, intracellular calcium concentrations ([Ca²⁺i]) are kept low (~0.1 mM), with extracellular calcium concentrations ([Ca²⁺e]) around ~2 mM. A significant elevation of [Ca²⁺i] (from 50–100 mM) is required for neurotransmitter release.
  2. Sources of Ca²⁺:
    • Extracellular: Influx through voltage-gated calcium channels.
    • Intracellular: Release from the endoplasmic reticulum (ER) due to activation of G-protein coupled receptors (GPCRs) that stimulate inositol trisphosphate (IP3) pathways.
  3. Diffusion Limitation: Ca²⁺ can only diffuse a maximum of 850 Å, necessitating that vesicles are docked and primed for rapid fusion once Ca²⁺ is elevated.

Mechanisms of Vesicle Release

Docking and Priming of Vesicles

  1. Trafficking to Active Zone: Vesicles are transported to the active zone of the synapse, similar to boats being brought into a docking bay.
  2. Tethering: Vesicles are loosely tethered at the active zone, which helps to concentrate them appropriately for release.
  3. Transient Docking: Vesicles become transiently docked at the active zone, optimizing exposure to Ca²⁺.
Priming Steps
  • Priming: This is followed by a series of molecular rearrangements that utilize ATP to create a partial SNARE complex. This complex is crucial for fusion:
    1. Vesicle SNARE proteins interact with pre-synaptic membrane SNARE proteins to prepare for fusion, akin to a zipper mechanism.
    2. When Ca²⁺ levels rise, vesicle protein Synaptotagmin detects the increase and facilitates the completion of the SNARE complex, leading to the merging of vesicle and terminal membranes, releasing the neurotransmitter into the cleft.

Synaptic Delays in Chemical Transmission

  1. Delays: Chemical transmission typically has a delay of about 0.5–1 msec from the arrival of an action potential (AP) at the pre-synaptic terminal to neurotransmitter binding at post-synaptic receptors.
  2. Comparison with Electrical Signalling: Electrical signalling can occur at speeds approaching the speed of light, whereas chemical synaptic transmission is notably slower.
  3. Efficiency Differences:
    • Peptidergic Transmission: Characterized by fewer pre-docked vesicles and a less efficient process requiring repetitive stimulation to accumulate enough Ca²⁺ for effective transmitter release, making it slower and less efficient compared to non-peptide synaptic processes.

Control of Post-Synaptic Responses

  1. Presynaptic Control: The size of depolarization at the presynaptic terminal directly influences the amount of Ca²⁺ entering, the number of vesicles released, and the amount of neurotransmitter that binds to post-synaptic receptors.
  2. Size of Response: The magnitude of the post-synaptic response will depend on these factors, illustrating the integral relationship between pre- and post-synaptic activity.

Recycling of Synaptic Vesicles

Process of Recycling

After neurotransmitter release, the recycling of vesicular membranes is essential due to the limited supply of synaptic vesicles in the terminal:

  1. Membrane Protein Removal: The membrane proteins of the vesicle are extruded, leaving only the lipid bilayer.
  2. Clathrin Coating: The remaining bilayer is coated with clathrin molecules that form a distinctive triskelion shape.
  3. Pinching Off: Dynamin protein pinches off the clathrin-coated vesicle from the terminal membrane.
  4. Lattice Formation: The clathrin forms a lattice of hexagons or pentagons around the vesicle.
  5. Internalisation: The vesicle is then internalised, allowing it to be recycled for future use.
Stages of Clathrin-Coated Pit Formation
  1. Stage 1: Initial coated membrane patch with slight curvature.
  2. Stage 2: Invaginated coated pit with a broad base.
  3. Stage 3: Invaginated coated pit with a narrow neck.
  4. Stage 4: Occasionally forms a ring-like structure around the narrow neck (low abundance).

These stages are crucial in defining the molecular cascade involved in synaptic vesicle recycling, revealing how the synapse manages its resources efficiently and effectively.

Life Cycle of a Neurotransmitter Vesicle

  1. Primary Active Transport: Utilizes V-class ion pumps to energize the vesicle trafficking process.
  2. Secondary Active Transport: Involves the neurotransmitter being transported into vesicles against its concentration gradient.

Post-Synaptic Responses and Receptors

Type of Receptors

  1. Membrane-Bound Receptors: Generally found in most synaptic interactions, they form ion channels and are essential for fast synaptic transmission.
    • Ion Channel Receptors: Composed of five protein subunits.
  2. G-Protein Coupled Receptors (GPCRs): A single polypeptide chain with seven trans-membrane segments which are linked to various G proteins, affecting multiple signalling pathways.
Classes of Receptors by Solubility
  • Hydrophilic (Water-Soluble) Receptors: Generally membrane-bound, forming ion channels or linked to G proteins or other signaling mechanisms.
  • Hydrophobic (Lipid-Soluble) Receptors: Typically intracellular, capable of binding to DNA and influencing gene transcription.

Fast and Slow Post-Synaptic Responses

Mechanism of Responses

  1. Fast Responses: Characterized by rapid onset (less than 5 ms), leading to quick changes in membrane potential, such as depolarization or hyperpolarization.
    • Examples: AP in Neuron 1 producing a rapid response in Neuron 3.
  2. Slow Responses: These responses unfold over a longer period (can take 20 seconds to initiate), with a gradual build-up and protracted effects.
    • Duration: Long-lasting effects (up to about 200 seconds).
    • Characteristics: Typically involve GPCR mechanisms and result in slower changes in neuronal activity compared to ionotropic signalling.

Excitatory and Inhibitory Synapses

Effects on Membrane Potential

  • Excitatory Post-Synaptic Potential (EPSP): Results from depolarization, increasing the likelihood of the post-synaptic neuron firing an action potential.
  • Inhibitory Post-Synaptic Potential (IPSP): Results from hyperpolarization, decreasing the likelihood of the action potential in the post-synaptic neuron.
  • Bidirectional Ion Movements: Changes in the post-synaptic potential result from net changes due to ion fluxes through large, non-selective receptor channels (neurotransmitter-gated channels).

Termination of Post-Synaptic Response

Mechanisms of Termination

The termination of neurotransmitter action at the post-synaptic site typically involves three main pathways:

  1. Reuptake Mechanisms: Transporters on the presynaptic or other adjacent membranes can take back neurotransmitters from the synaptic cleft (Note: This mechanism is unavailable for peptide transmitters).
  2. Enzymatic Degradation: Enzymes can break down neurotransmitters in the synaptic cleft, making them inactive.
  3. Diffusion: Neurotransmitters can simply diffuse away from the synaptic cleft, reducing their concentration and effect on post-synaptic receptors.

This detailed overview of chemical synaptic signalling illustrates the complexities and intricacies of neurotransmitter dynamics, vesicle trafficking, synaptic delays, and the multifunctional roles receptors play in neuronal communication.