Neurotransmitters

NEUROTRANSMITTERS

A LITTLE ORGANIC CHEMISTRY

• Amines: Derivatives of ammonia classified as primary, secondary, or tertiary.

• Amino Acids: Organic compounds consisting of:

  • An amino group (–NH2)

  • A carboxylic group (–COOH)

  • An "R" group which is unique for each amino acid.

• Peptides: Chains of amino acids linked together.

CLASSES OF NEUROTRANSMITTERS

• Families and Subfamilies:

  1. Amines

     • Quaternary amines

     • Monoamines

     • Catecholamines

     • Indolamines

  2. Amino Acids

  3. Neuropeptides

     • Opioid peptides

     • Other neuropeptides

  4. Gases

NEUROTRANSMITTER SYNTHESIS

• Small molecule neurotransmitters vs. Neuropeptides

  • Cargo Movement: Utilizes motor proteins and microtubules to transport vesicles along the axon.

  • Small-Molecule Transmitters:

    1. Synthesized in the cell body

    2. Slow axonal transport

  • Peptide Transmitters:

    • Synthesis and packaging occur in the neuron terminal with enzymes modifying pre-peptides.

    • Released neurotransmitter diffuses away and may be degraded.

AXONAL TRANSPORT

• Process by which neurotransmitters and associated components are transported via axons to synaptic terminals.

NECESSARY FEATURES OF CHEMICAL SYNAPSE

• Core components include:

  • Neurotransmitter or ligand

  • Vesicles

  • Calcium influx: Triggers release of neurotransmitters

  • Proximity: Between pre- and postsynaptic neurons

  • Receptors: Located in the postsynaptic neuron that bind neurotransmitters.

• Process:

  • Calcium ions cause synaptic vesicles to release neurotransmitters into the synaptic cleft.

VESICLE DOCKING AND EXOCYTOSIS

• SNARE proteins: Facilitate the exocytosis and endocytosis at the synapse in a dependent manner.

• Include:

  • Synaptobrevin

  • SNAP-25

  • Syntaxin

FUSION OF VESICLES

• Vesicles must fuse with the presynaptic membrane to release neurotransmitters effectively into the synaptic cleft.

TYPES OF RECEPTORS

• Presynaptic receptors: Autoreceptors regulating neurotransmitter release.

• Postsynaptic receptors:

  • Ionotropic: Fast-acting receptors that open ion channels.

  • Metabotropic: Slower receptors that work via G-proteins to influence other cellular processes.

IONOTROPIC AND METABOTROPIC RECEPTORS

• Ionotropic receptors: Directly linked to ion channels; fast responses.

• Metabotropic receptors: Indirectly linked to ion channels; slower, longer-lasting effects.

SUMMARY OF ION CHANNELS SO FAR...

• Various types of ion channels exhibit distinct activation mechanisms:

  • Resting K+ channel: Always open.

  • Voltage-gated channel: Opens in response to membrane potential changes.

  • Ligand-gated channel: Opens in response to specific neurotransmitters.

  • Signal-gated channel: Opens in response to intracellular molecules.

INTRACELLULAR EFFECTS OF GPCR ACTIVATION

• GPCRs (G-protein-coupled receptors) activate various intracellular pathways involving:

  • GTP: Acts as a molecular switch in signaling cascades.

  • Intracellular messengers: Different cascades are influenced leading to diverse cellular outcomes.

NEUROTRANSMITTER CLEARANCE

• Life Cycle of Neurotransmitter includes:

  1. Synthesis in cell body or terminal.

  2. Packaging into vesicles.

  3. Release into synaptic cleft.

  4. Activation of postsynaptic receptors.

  5. Clearance by:

     • Reuptake: Retrieval back into the presynaptic neuron.

     • Metabolism: Breakdown by enzymes.

     • Diffusion: Movement away from the synapse without reuptake.

ELECTRICAL SYNAPSES

• Distinction from chemical synapses:

  • Chemical Synapse:

    • Uses neurotransmitters for signaling (e.g., Glutamate)

    • Involves more complex regulation such as CaMKII.

  • Electrical Synapse:

    • Direct gap junctions enabling electrical signal transmission between neurons.

NEUROTRANSMITTERS SUMMARY

• Amines:

  • Dopamine

  • Serotonin

  • Acetylcholine

  • Norepinephrine

• Amino Acids:

  • Glutamate

  • GABA

• Peptides:

  • Opioids

  • Oxytocin

DOPAMINE

• Pathways include:

  • Mesolimbic tract

  • Nigrostriatal tract

  • Mesocortical tract

  • Tuberoinfundibular tract

• Synthesized from Phenylalanine through enzymatic steps involving Tyrosine.

NOREPINEPHRINE

• Originates from the locus coeruleus and affects various bodily functions:

  • Vasoconstriction

  • Increased blood pressure

  • Regulation of autonomic functions.

SEROTONIN

• Produced in various brain regions especially the raphe nuclei.

• Involves tryptophan as a precursor and has multiple receptor subtypes influencing mood and behavior.

ACETYLCHOLINE

• Major neurotransmitter in both the central and peripheral nervous system.

• Has both nicotinic and muscarinic receptors influencing muscle action and the parasympathetic system.

ACETYLCHOLINE RECEPTORS

• Nicotinic receptors: Ligand-gated ion channels enabling depolarization.

• Muscarinic receptors: G-protein-coupled receptors producing parasympathetic effects.

GLUTAMATE

• Major excitatory neurotransmitter in the brain with various receptor types (e.g., NMDA, AMPA).

• Critical in synaptic plasticity and learning processes.

GABA (Gamma-Aminobutyric Acid)

• Primary inhibitory neurotransmitter in the brain, aiding in the regulation of neuronal excitability.

OPIOIDS

• Endogenous peptides that modulate pain, stress response, and reward pathways.

OXYTOCIN

• Hormone and neurotransmitter involved in reproductive functions, social bonding, and emotional responses.

GASES

• Gaseous neurotransmitters (e.g., Nitric Oxide) act as signaling molecules in the nervous system influencing various physiological responses.