Neurotransmitters and Receptors

NT Fundamentals - Chemical Messenger Intro

• Neurotransmitter (NT): Chemical messenger crossing synapse.
• Key Criteria: Presynaptic synthesis & storage, $Ca^{2+}$-dependent release, specific postsynaptic receptors, rapid inactivation.
• Classification:
  • Chemical: ACh, amino acids (Glu, GABA), biogenic amines (DA, 5-HT), peptides.
  • Functional: Excitatory (Glu), Inhibitory (GABA).
• Lifecycle:
  • Synthesis, vesicular storage (VMAT/VAChT).
  • $Ca^{2+}$-triggered release (SNAREs).
  • Receptor binding.
  • Termination: Reuptake (SERT, DAT, NET) or enzymatic degradation (AChE, MAO, COMT).

⭐ Botulinum toxin blocks ACh release by cleaving SNARE proteins.

Excitatory/Inhibitory NTs - Go & Stop Signals

• Excitatory NTs (Go Signals):
  • Acetylcholine (ACh):
    • Synth: ChAT (Choline Acetyltransferase); Degrad: AChE (Acetylcholinesterase).
    • Receptors:
      • Nicotinic (Ionotropic, ligand-gated ion channels): Nn (neurons), Nm (neuromuscular junction).
      • Muscarinic (Metabotropic, G-protein coupled): M1-M5. 📌 QIQSIQ Mnemonic: M1, M3, M5 ($G_q$); M2, M4 ($G_i$).
  • Glutamate:
    • Major excitatory NT in CNS.
    • Receptors:
      • Ionotropic: AMPA, NMDA (require glycine, voltage-dependent $Mg^{2+}$ block, $Ca^{2+}$ influx), Kainate.
      • Metabotropic: mGluRs.
    • Role in excitotoxicity (excessive stimulation).
• Inhibitory NTs (Stop Signals):
  • GABA (γ-aminobutyric acid):
    • Major inhibitory NT in brain. Synth from glutamate by GAD (Glutamic acid decarboxylase).
    • Receptors:
      • GABA-A (Ionotropic, $Cl^{-}$ channel): Target for benzodiazepines, barbiturates.
      • GABA-B (Metabotropic, $K^{+}$ channel via $G_i$/$G_o$).
  • Glycine:
    • Major inhibitory NT in spinal cord & brainstem.
    • Receptor: Ionotropic, $Cl^{-}$ channel (blocked by strychnine).

⭐ NMDA receptors: unique for voltage-dependent magnesium block & glycine co-agonism, enabling calcium influx crucial for synaptic plasticity (e.g., LTP).

Neuromodulators - Brain's Volume Knobs

• Monoamines: Broadly acting neurotransmitters.
  • Catecholamines (Tyrosine precursor):
    • Dopamine (DA):
      • Pathways: 📌 Nigrostriatal (motor); Mesolimbic/cortical (reward, psychosis); Tuberoinfundibular (↓prolactin).
      • Receptors: D1-like ($G_s$), D2-like ($G_i$).
      • Clinical: Parkinson's (↓DA), Schizophrenia (↑DA).
    • Norepinephrine (NE): Locus Coeruleus. Receptors: α & β adrenergic. Arousal, mood, sympathetic NS.
    • Epinephrine (Adrenaline): Adrenal medulla, minor CNS role.
  • Indolamines:
    • Serotonin (5-HT): (Tryptophan precursor). Raphe Nuclei. Receptors (e.g., 5-HT1A, 5-HT2A, 5-HT3). Mood, sleep, anxiety. SSRIs.
  • Histamine: Hypothalamus. Arousal, wakefulness.
• Peptide NTs:
  • Opioids (Endorphins, Enkephalins, Dynorphins): Analgesia.
  • Substance P: Pain transmission.
• Other NTs:
  • Nitric Oxide (NO): Retrograde messenger. Synthesized by NOS. Activates guanylyl cyclase $\rightarrow \uparrow cGMP$.
  • Adenosine: Purinergic. Generally inhibitory. Caffeine antagonist.

⭐ Most antipsychotic drugs act by blocking D2 dopamine receptors.

Receptors & Clinical Ties - Locks, Keys & Cures

Receptors are pivotal in neurotransmission, mediating cellular responses. Two main classes:

-   Gs: ↑cAMP
-   Gi: ↓cAMP
-   Gq: ↑IP3/DAG, $Ca^{2+}$

• Clinical Ties & Pharmacology:
  • Myasthenia Gravis: Antibodies vs. Nicotinic AChR (Nm) at NMJ. Tx: AChE inhibitors (e.g., Neostigmine).
  • Parkinson's Disease: ↓Dopamine in nigrostriatal pathway. Tx: L-DOPA (precursor), DA agonists.
  • Depression/Anxiety: Imbalance in Serotonin (5-HT), Norepinephrine (NE). Tx: SSRIs, SNRIs.
  • Schizophrenia: Dopamine hypothesis (excess D2 activity). Tx: Antipsychotics (D2 receptor antagonists).

⭐ Myasthenia gravis is characterized by antibodies against nicotinic acetylcholine receptors at the neuromuscular junction.

High‑Yield Points - ⚡ Biggest Takeaways

• Acetylcholine (ACh): Key at NMJ (nicotinic, muscarinic receptors); deficient in Myasthenia Gravis (anti-AChR Abs).
• Glutamate: Main excitatory CNS neurotransmitter (NMDA, AMPA receptors).
• GABA: Main inhibitory CNS neurotransmitter (GABA-A: Cl- influx; GABA-B: K+ efflux/Ca2+ block).
• Dopamine: Crucial for motor control (Parkinson''s ↓) and reward (schizophrenia ↑).
• Serotonin (5-HT): Regulates mood, sleep, appetite; targeted by SSRIs.
• Norepinephrine: Key in sympathetic responses; acts on α & β adrenergic receptors.
• Catecholamine synthesis: Tyrosine is precursor; degradation by MAO & COMT enzymes.