acetylcholine

ACETYLCHOLINE (ACh)

  • Discovery:

    • By Otto Loewi in 1921; demonstrated that the vagus nerve secreted a substance that inhibited heart muscle.

    • Awarded the Nobel Prize in 1936 for this discovery.

  • Chemical Structure:

    • Composed of an acetate group and a choline group.

FUNCTIONS OF ACETYLCHOLINE

  • Key Neurotransmitter (NT) in the Peripheral Nervous System (PNS):

    • Important for several functions in the Nervous System.

  • Autonomic Nervous System (ANS):

    • Sympathetic System: A part of the ANS that prepares the body for stressful or emergency situations.

    • Parasympathetic System: A part of the ANS that conserves energy and restores the body to resting state.

  • Somatic Nervous System:

    • Controls voluntary muscle movements.

  • Neuromuscular Junction:

    • Synapse between motor neurons and muscles, where ACh plays a crucial role.

  • Toxicity Levels of ACh:

    • Both an excess and deficiency of ACh can be lethal.

SYNTHESIS OF ACETYLCHOLINE

  • Process:

    • Choline and acetyl CoA are converted to acetylcholine through the action of the enzyme choline acetyltransferase (ChAT).

  • Note:

    • Excess choline can lead to a “fishy” smell caused by trimethylamine.

PACKAGING OF ACETYLCHOLINE

  • Storage:

    • ACh is transported to synaptic vesicles for later release.

    • Each vesicle can store several thousand ACh molecules.

  • Vesicular ACh Transporter (VAChT):

    • A protein that moves ACh into vesicles.

    • Blocker: Vesamicol can inhibit VAChT, resulting in reduced ACh release.

RELEASE OF ACETYLCHOLINE

  • Mechanisms of Release:

    • Certain drugs can cause the release of ACh without an action potential (e.g., black widow spider venom leading to chest pain, tremors, nausea, and excessive salivation due to massive ACh release).

    • Other substances, like botulinum toxin (Botox), inhibit the ACh release, causing muscle weakness and paralysis, making it one of the most potent toxins known.

METABOLISM OF ACETYLCHOLINE

  • Breakdown:

    • ACh in the synapse is broken down by the enzyme acetylcholinesterase (AChE) into choline and acetic acid.

  • Pharmacological Interventions:

    • AChE inhibitors (like donepezil, used in dementia treatment) block this breakdown, leading to increased ACh levels.

    • Nerve gases such as sarin also act as AChE inhibitors, raising ACh levels dangerously.

REUPTAKE OF ACETYLCHOLINE

  • Mechanism:

    • Choline reuptake occurs via a choline transporter, allowing ACh to be remade and repackaged for further use.

    • Drugs like hemicholinium-3 can block ACh reuptake, which is highly toxic.

ACh PATHWAYS

  • Distribution and Functionality:

    • ACh is involved in both neuromuscular (somatic) and autonomic motor systems.

    • Parasympathetic Pathways: Involves preganglionic and postganglionic fibers.

    • Sympathetic Pathways: Primarily involve preganglionic pathways.

  • Brain Pathways:

    • ACh neurons cluster in several brain areas, transmitting fibers to various brain regions, featuring varicosities similar to dopamine.

ACh RECEPTORS

  • Types of ACh Receptors:

    • Ionotropic Nicotinic ACh Receptors (nAChRs):

    • Allow influx of Na+ and Ca2+, and efflux of K+, leading to depolarization and excitatory effects.

    • Commonly found at neuromuscular junctions, peripheral nervous system neurons in the ANS, and various brain regions.

    • Function in enhancing neurotransmission by depolarizing axon terminals.

  • Drug Interactions with nAChRs:

    • Agonist: Nicotine (from tobacco) is a potent stimulant and highly addictive.

    • Antagonists: Include coniine, a toxic element from hemlock known for causing respiratory failure, and d-tubocurarine from curare, utilized in blow-darts.

  • Metabotropic Muscarinic ACh Receptors (mAChRs):

    • Five types: M1, M3, M5 (typically excitatory) and M2, M4 (typically inhibitory).

    • Example: M2 slows heart rate in the parasympathetic division.

    • Antagonist Example: Atropine from the nightshade plant.

GLUTAMATE (Glu)

  • Description:

    • A basic amino acid with high concentrations in the brain; acknowledged as a neurotransmitter in the 1980s.

  • Discovery:

    • By Takashi Hayashi in 1954, who found that glutamate injection into the brain resulted in seizures.

SYNTHESIS OF GLUTAMATE

  • Process:

    • Glutamine is converted to glutamate via the enzyme glutaminase, which utilizes ATP.

    • Chemical Reaction:
      (extGlutamine+extH<em>2extO+extATPightarrowextGlutamate+extNH</em>3+extADP+extPO43−)( ext{Glutamine} + ext{H}<em>2 ext{O} + ext{ATP} ightarrow ext{Glutamate} + ext{NH}</em>3 + ext{ADP} + ext{PO}_4^{3-})

PACKAGING OF GLUTAMATE

  • Storage:

    • Glutamate is moved into synaptic vesicles for later release, with about 8000 molecules per vesicle.

  • Vesicular Glutamate Transporter (VGLUT):

    • A protein facilitating glutamate transport into vesicles.

    • Three types (VGLUT1, VGLUT2, VGLUT3), which serve as markers for glutamatergic neurons.

REUPTAKE OF GLUTAMATE

  • Mechanism:

    • Occurs via astrocytes utilizing excitatory amino acid transporters (EAATs), with five different types (EAAT1 to EAAT5).

    • Converts glutamate back into glutamine via glutamine synthetase and then transported into neurons for reconversion to glutamate.

GLUTAMATE RECEPTORS

  • Ionotropic Receptors:

    • Consist of three types: AMPA, kainate, and NMDA, all of which depolarize the membrane inducing an excitatory response.

    • AMPA and Kainate Receptors: They allow Na+ influx.

  • NMDA Receptors:

    • Allow both Na+ and Ca2+ influx, with Ca2+ acting as a secondary messenger.

    • Co-agonists: Both glutamate and glycine must bind for activation.

    • At resting membrane potential (-60 mV), Mg2+ blocks the NMDA channel from opening; depolarization is required to expel Mg2+, functioning as a coincidence detector.

GLUTAMATE RECEPTORS AND MEMORY

  • Hippocampal Anatomy:

    • Relating to CA3 and CA1 neurons, schaffer collaterals.

  • Long-Term Potentiation (LTP):

    • A process involving the strengthening of synaptic connections resulting in larger EPSPs in the postsynaptic neuron, particularly in CA1 cells due to rapid action potentials from CA3 neurons.

  • Mechanism of LTP:

    • Tetanus leads to sustained increased EPSP strength in CA1 neurons.

    • NMDA receptor activation leads to Ca2+ entering the neuron, prompting the addition of more AMPA receptors at the postsynaptic membrane, enhancing EPSP response.

  • Pharmacological Agents Affecting NMDA:

    • Drugs such as phencyclidine (PCP) and ketamine act as uncompetitive NMDA receptor antagonists but do not prevent agonist binding.

  • Metabotropic Glutamate Receptors (mGluRs):

    • Eight types mGluR1 to mGluR8; some function as autoreceptors inhibiting glutamate release and participate in various functions like motor control, cognition, mood regulation, and pain perception.

MONOSODIUM GLUTAMATE (MSG)

  • Description:

    • A widely used food additive known for enhancing flavor, generally regarded as safe and does not easily cross the blood-brain barrier (BBB).

  • Example Product:

    • Doritos, with ingredients including MSG.

GAMMA-AMINOBUTYRIC ACID (GABA)

  • Functionality:

    • Functions strictly as a neurotransmitter and is found in high concentrations in the brain.

    • Discovered by Eugene Roberts in 1950.

SYNTHESIS OF GABA

  • Process:

    • GABA is synthesized through the conversion of glutamate via glutamic acid decarboxylase (GAD).
      extGlutamicacid<br>ightarrowexty−aminobutyricacid(GABA)+extCO2ext{Glutamic acid} <br>ightarrow ext{y-aminobutyric acid (GABA)} + ext{CO}_2

PACKAGING OF GABA

  • Transport:

    • GABA is moved into vesicles by the vesicular GABA transporter (VGAT or VIAAT).

REUPTAKE OF GABA

  • Mechanism:

    • GABA transporters (GAT1, GAT2, GAT3) in astrocytes account for GABA reuptake, with GAT1 majorly involved in neuron reuptake.

    • Drugs: Tiagabine (Gabitril) blocks GAT1, increases GABA in the synaptic cleft, serves as an antiseizure medication but may cause dizziness.

METABOLISM OF GABA

  • Biochemical Breakdown:

    • GABA is metabolized via several steps; with GABA aminotransferase (GABA-T) considered a key enzyme that converts GABA to succinate.

    • Drug Intervention: GABA-T inhibitors (such as vigabatrin, used for epilepsy) can interfere with metabolism.

GABA RECEPTORS

  • Types:

    • Ionotropic GABA Receptors (GABAA):

    • Allow Cl- influx into the cell, leading to inhibition via inhibitory post-synaptic potentials (IPSPs) and preventing the firing of action potentials.

  • Agonist Drugs for GABAA:

    • Include muscimol, benzodiazepines, barbiturates, and ethanol (alcohol) which serve as antianxiety, sedative, and muscle relaxants.

  • GABAB Receptors:

    • Metabotropic receptors that can act as autoreceptors; drugs such as baclofen (Lioresal) serve as muscle relaxants and antispastic agents.