Neuronal Communication II: Neurotransmitters & Neuromodulators

• A neuromodulator is a subset of neurotransmitters that can affect many neurons at once (whole groups), not just the one cell across the cleft.
• It is released diffusely → volume transmission:
  • Release can happen away from the synapse (e.g., from varicosities along the axon).
  • Even if released at a synapse, it diffuses out of the cleft to neighboring cells.
• Receptors: usually metabotropic (GPCRs) → longer-lasting effects; often located off to the side of the synapse or on the presynaptic terminal.
• Effect: it does not necessarily carry excitation or inhibition itself — it changes how strongly other transmitters act (turns the volume up or down).
• Classic example (presynaptic modulation): one terminal releases a neuropeptide from dense-core vesicles → it diffuses laterally to a neighboring terminal → binds presynaptic GPCRs → enhances release of that terminal's small-molecule transmitter.

• Defining features of a neuromodulator:
  • Affects many neurons at the same time → diffuse release = volume transmission, away from the synapse.
  • Acts through metabotropic receptors → longer-lasting effect; often presynaptic.
  • Modifies the effect of other transmitters rather than carrying excitation/inhibition itself.
• The seven neuromodulatory groups: neuropeptides → lipid retrograde transmitters → DA → NE → 5-HT → histamine → ACh.

• Quick sort for "which class does X belong to?":
  • Amino acids: Glu, Asp, GABA, Gly.
  • Catecholamines: DA, NE, Epi; other biogenic amines: 5-HT, histamine.
  • ACh (own group).
  • Neuropeptides: NPY, vasopressin, substance P, ACTH, orexin, opioid peptides (five categories, next question).
  • Lipid retrograde: endocannabinoids.

Learn this skeleton once, then just fill in the blanks for each transmitter. Every drug question is "which step does it hit?"

Master table

• Receptors: nicotinic = ligand-gated cation (Na⁺/K⁺) channel (excitatory, fast); muscarinic M1–M5 = GPCRs.
• Unique point: ACh is the only classic small-molecule transmitter destroyed in the cleft by an enzyme rather than taken back up whole; it is the choline that gets recycled.

• Synthesis: glutamine → glutamate by mitochondrial glutaminase (rate-limiting in the summary table). Glutamate can also come from the TCA cycle (α-ketoglutarate).
• Storage: VGLUT into small clear vesicles → Ca²⁺-dependent release.
• Termination: excitatory amino acid transporters (EAATs), mostly on astrocytes → astrocyte glutamine synthetase turns it into glutamine → glutamine returned to the neuron (glutamate–glutamine cycle).
• Receptors:
  • Ionotropic (always excitatory): AMPA (Na⁺, fast EPSP), kainate (Na⁺), NMDA (Na⁺ and Ca²⁺; needs glycine co-agonist + depolarization to pop out the Mg²⁺ block).
  • Metabotropic: mGluR 1–8 (GPCRs).

1. Precursor: glutamate, itself produced from glucose via the TCA cycle (and from glutamine).
2. Glutamic acid decarboxylase (GAD) converts glutamate → GABA = rate-limiting; needs pyridoxal phosphate (vitamin B6). GAD is only in GABAergic neurons (a marker for them).
3. Active transport into vesicles (VIAAT).
4. Ca²⁺-triggered exocytosis; GABA can also diffuse away from the immediate postsynaptic site (reaching extrasynaptic receptors).
5. Removal: reuptake by the GABA transporter (GAT) on astrocytes and presynaptic neurons.
6. Astrocytes convert GABA → glutamine, which is released and taken up by neurons to make glutamate → GABA again = GABA/glutamine cycle.

• Where GABA receptors sit: neuron cell body (quick shut-off of AP firing), dendritic shaft, extrasynaptic sites, and presynaptic autoreceptors.
• Overall effect of GABA: transient inhibition of AP firing. Fun fact: GABA is excitatory in the developing brain (immature neurons have high intracellular Cl⁻, so opening Cl⁻ channels depolarizes).

1. Precursor: serine → glycine by serine hydroxymethyltransferase (rate-limiting).
2. Loaded into vesicles by the same transporter used by GABA (VIAAT).
3. Ca²⁺-triggered exocytosis.
4. Reuptake by glycine transporters on astrocytes and presynaptic neurons; astrocytes turn glycine back into serine, which is released for neuronal reuptake.

• Receptors: ionotropic ONLY: several subtypes of glycine-gated Cl⁻ channels, pentamers like GABA-A → Cl⁻ in → inhibition.
• Location: brainstem and spinal cord; about ½ of spinal inhibitory synapses use glycine.
• Strychnine blocks the glycine receptor (closes the pore) → loss of inhibition → convulsions.
• Glycine is also a co-agonist at NMDA receptors.
• Clinical: mutations in glycine transporter or degradation-enzyme genes → hyperglycinemia, a devastating neonatal disease (lethargy, seizures, cognitive deficits).

1. Tyrosine → L-DOPA by tyrosine hydroxylase (rate-limiting, cytoplasm).
2. L-DOPA → dopamine by DOPA decarboxylase = aromatic L-amino acid decarboxylase (AADC).
3. Dopamine pumped into vesicles by VMAT.
4. Inside the vesicle, dopamine β-hydroxylase (DBH) makes NE. DBH identifies NE neurons. NE is the only transmitter whose last synthetic step happens inside the vesicle.
5. In epinephrine neurons (and adrenal medulla), NE leaks out to the cytoplasm → PNMT → epinephrine → transported back into vesicles.

1. Precursor: tryptophan → 5-hydroxytryptophan by tryptophan-5-hydroxylase (rate-limiting).
2. 5-HTP → serotonin (5-hydroxytryptamine) by aromatic L-amino acid decarboxylase (AADC).
3. VMAT loads vesicles → Ca²⁺ exocytosis → diffuses across cleft to receptors.
4. Removed by the specific presynaptic transporter SERT → metabolized by MAO or reloaded into vesicles.

1. Histidine → histamine by histidine decarboxylase (rate-limiting).
2. VMAT loads vesicles → Ca²⁺ exocytosis.
3. Metabolized by MAO and histamine methyltransferase.

• Receptors: four types (H1–H4), all metabotropic.
• CNS histamine neurons are in the hypothalamus (tuberomammillary nucleus) → sparse but widespread projections to almost all brain areas and the spinal cord.
• Functions: arousal and attention; controls reactivity of the vestibular system.
• Peripheral histamine from mast cells → allergic responses. Antihistamines that cross the BBB (diphenhydramine, Benadryl) are sedatives (↓arousal).

• Synthesis: in the cell body as large pre-propeptides (RER → Golgi) → packaged into dense-core vesicles → axonal transport to the terminal.
• Processing: signal sequence cleaved → proteolytic cleavage can yield several active peptides from one precursor (diversity); further processing can even occur after release.
• Release: Ca²⁺-dependent, but needs high-frequency firing (see LO 6).
• Receptors: GPCRs only, very high affinity → act at low concentrations; synaptic and extrasynaptic → modulatory.
• Termination: extracellular endo- and exopeptidases; renewal requires new synthesis in the soma.
• Roles: NPY → starting and maintaining feeding (satiety/obesity); peptides also in anxiety/panic, analgesia, and regulating sympathetic ganglion output and gut activity.
• Neuropeptides can be co-localized with small-molecule transmitters in the same terminal (e.g., opioids with GABA).

Opioids: depressants and analgesics

• What they are: anandamide (AEA) and 2-arachidonoylglycerol (2-AG), unsaturated fatty acids with polar head groups.
• Made on demand by enzymatic breakdown of membrane lipids in the postsynaptic neuron when Ca²⁺ activates a second-messenger cascade.
• Released by simply diffusing through the membrane (not stored in vesicles, yet release is still Ca²⁺-dependent) → bind presynaptic CB1 receptors = retrograde signaling.
• Terminated by hydrolysis: fatty acid amide hydrolase (FAAH).
• Receptors: metabotropic only, Gi-coupled → inhibitory on the target (presynaptic) neuron → transient or long-lasting ↓ transmitter release.
• Affect appetite, pain sensation, mood and memory.
• Exogenous cannabinoid: Δ⁹-tetrahydrocannabinol (THC) from Cannabis.

Ion carried by each ionotropic receptor: nicotinic ACh → Na⁺ · AMPA, kainate → Na⁺ · NMDA → Na⁺ and Ca²⁺ · 5-HT3 → Na⁺ · GABA-A, glycine → Cl⁻.

• Most inhibitory synapses in brain and spinal cord use GABA or glycine; overall GABA effect = transient inhibition of AP firing.
• Ionotropic glutamate, nicotinic ACh and 5-HT3 receptors are excitatory.
• CNS depressants (alcohol, benzodiazepines, barbiturates, anesthetics, zolpidem) → enhance GABA.
• Blocking inhibition → seizures/convulsions: picrotoxin, bicuculline (block GABA) and strychnine (blocks glycine).

• The four core differences (small molecule vs neuropeptide):
  1. Site of synthesis and packaging into vesicles (terminal vs soma).
  2. Diffusion (nanometers vs micrometers).
  3. Termination mechanism (reuptake/enzymes vs peptidases).
  4. Magnitude of stimulus required for release (single AP vs high-frequency train).