Neurotransmitter Criteria

Dale's Principle

Dale's principle states that all terminals of the same neuron release the same neurotransmitter(s). 

Although this has sometimes been interpreted to mean one neuron-one neurotransmitter, most if not all neurons contain and secrete more than one neurotransmitter.

1.  Neuropeptides largely co-exist in the same cells as other neurotransmitters.

3.   Peptide and amine neurotransmitters can be controlled independently.

Overview of Neurotransmission

  • Synthesis of enzymes and/or or precursors in cell body and transport to the terminal

  • Synthesis of neurotransmitter in nerve terminal

  • In vesicles in nerve terminal

  • In vesicles in cell body which are transported to terminal 

  • Depolarization of presynaptic terminal

  • Opening of Ca2+ channels and influx of Ca2+

  • Vesicle fusion with presynaptic membrane

  • Exocytosis of neurotransmitter

•Reception

  • Binding to postsynaptic receptor

  • Binding to presynaptic autoreceptor

  • Breakdown or metabolism

  • Reuptake into presynaptic neuron

  • Internalization in postsynaptic neuron

Synthesis of Small Molecule Transmitters

Storage of of Small Molecule Transmitters

• Packaging of neurotransmitters into synaptic vesicles

• Small, clear core vesicles about 40-60 nm in diameter

• Some final processing of transmitter may occur in the vesicle

• Protects transmitter from degradation

• Transmitters are stored in vesicles until release following an action potential.

Synthesis of Peptide Transmitters

Storage of of Peptide Transmitters

• Peptides or precursors synthesized long distance away from release

• Stored in large dense core vesicles (90-250 nm in diameter) formed within trans-Golgi

• ATP-dependent transport down microtubule tracks to the terminal

• In terminal, final processing of transmitter will occur within the vesicle

Neurotransmitter Release

• Depolarization causes opening of voltage gated Ca2+ channels

• Influx of Ca2+ though channels

• Ca2+ causes vesicle to fuse with presynaptic membrane

• Transmitter released

Neurotransmitter Release by Synaptic Vesicles

• Vesicle flattens; becomes part of synaptic membrane

• Content emptied fully into synaptic cleft

• Vesicle membrane reinternalized via clathrin-dependent endocytosis

2) Fleeting Fusion

• ”Kiss and Run” or “Flicker Fusion”

• Transient fusion pore briefly connects vesicle and the membrane

• Rapid release

Inactivation

  • Important to terminate the response

  • Allows new signals to be received

  • temporal resolution of new information

  • Continued exposure can lead to desensitization of receptors

• some fraction of all transmitters diffuses from synapse

• peptides show high degree of diffusion

2.  Reuptake into presynaptic neuron

• Specific to neurons using that neurotransmitter

  Na+-dependent transporters

  High affinity

  Found for DA, NE, 5-HT, glutamate, GABA, glycine, choline

  Complicated structure -12 membrane spanning domains and multiple glycosylation sites

• Non-specific neurons and glia

  Na+-independent

Note there can also be internalization in postsynaptic neuron

3. Enzyme degradation (metabolism)

  • May control amount of transmitter in synapse or inactivate transmitter that has diffused away (i.e, monoamine oxidase (MAO))

  • Some metabolism occurs in presynaptic neuron after reuptake (especially for biogenic amines)

  • Peptides degraded by peptidases

Special Aspects of Peptide Neurotransmission

1.  Synthesis of precursor proteins occurs on ribosomes in the perikarya; the peptide products are transported axoplasmically to the nerve terminals.

2.  Release occurs by exocytosis only.

3.  Peptides have high specificity and affinity for their receptors, enabling release of small amounts to be effective, and permitting actions remote from the site of release.

4.  Inactivation occurs by degradation; there is no good evidence for re-uptake.

5.  Peptides can have very specific behavioral and physiological effects.