Neurotransmitters are intercellular messengers categorized into conventional and unconventional types based on their storage and release mechanisms.

Classification of Neurotransmitters

• Conventional Neurotransmitters: These are stored in synaptic vesicles (SVs) and released by Ca 2+ -dependent exocytosis. They include:

  • Small-Molecule Transmitters: Acetylcholine (ACh), purines like ATP, and amino acids such as glutamate (the main excitatory transmitter in the brain), GABA, and glycine (inhibitory).

  • Biogenic Monoamines: These include catecholamines (dopamine, norepinephrine, and epinephrine) derived from tyrosine, serotonin (derived from tryptophan), and histamine.

  • Neuropeptides: Large molecules ranging from 3 to 100 amino acids, such as substance P, enkephalins, and cholecystokinin (CCK), often stored in large dense-core vesicles.

• Unconventional Neurotransmitters: These are not stored in vesicles but are synthesized and released "on demand". They include:

  • Gases: Nitric oxide (NO) and carbon monoxide (CO), which are highly membrane-permeant and diffuse directly to target cells.

  • Lipids: Endocannabinoids like 2-AG and anandamide, which often function as retrograde messengers by traveling from the postsynaptic neuron back to the presynaptic terminal.

Mechanisms of Chemical Transmission

Chemical synaptic transmission is a unidirectional, polarized process occurring in seven discrete steps:

1. Synthesis and Storage: Neurotransmitters are synthesized in the nerve terminal or cell body and packaged into SVs. This packaging often uses a V-ATPase to create an H+ gradient that powers secondary active transporters.

2. Action Potential Arrival: An action potential travels down the axon and depolarizes the presynaptic terminal.

3. Ca 2+ Influx: Depolarization opens voltage-gated Ca 2+ channels, allowing Ca 2+ to flow into the terminal down its electrochemical gradient.

4. Exocytosis: The rise in intracellular Ca 2+ is sensed by the protein synaptotagmin, which triggers the fusion of docked vesicles with the presynaptic membrane via the SNARE complex (synaptobrevin, syntaxin, and SNAP-25).

5. Diffusion: The neurotransmitter is released in fixed quantal packets and diffuses across the synaptic cleft, which is typically 20 to 40 nm wide.

6. Receptor Activation: The transmitter binds to specific postsynaptic receptors, which are classified as:

   • Ionotropic: Ligand-gated ion channels that cause rapid changes in membrane potential, such as depolarizing EPSPs or hyperpolarizing IPSPs.

   • Metabotropic: G-protein–coupled receptors that initiate slower intracellular signaling cascades, often involving second messengers like cAMP or IP3.

7. Termination: The signal is ended by removing the transmitter through diffusion, enzymatic degradation (e.g., acetylcholinesterase), or reuptake by Na+ -dependent transporters into neurons or glia.