OE

Week 5 ELM 10: Neurotransmitters

Receptors: Basic Concepts

  • A receptor binds an information-carrying molecule called an agonist.
    • Examples of agonists include neurotransmitters and hormones.
  • The receptor then "passes on the information" in a different form through a process called transduction.
    • This process changes cell behavior.
    • An example is the nicotinic acetylcholine receptor.
  • Acetylcholinesterase is also mentioned, likely in the context of modulating acetylcholine signaling.

Receptor Types

  • Ligand-gated ion channels: Allow ions to flow across the cell membrane upon ligand binding.
  • G protein-coupled receptors (GPCRs) or metabotropic receptors: Activate G proteins upon ligand binding, leading to downstream signaling cascades.
  • Receptor tyrosine kinases: Phosphorylate tyrosine residues on target proteins upon ligand binding, initiating signaling pathways.
  • Nuclear hormone receptors: Regulate gene transcription in the nucleus upon ligand binding.

G Protein-Coupled Receptors (GPCRs)

  • GPCRs have a structure of 7 transmembrane α-helices.
  • They possess an agonist-binding site and a G-protein binding domain.

GPCR Activation and Signal Amplification

  • Agonist binding to the GPCR facilitates the exchange of GDP for GTP on the G protein α subunit.
  • Activated G protein interacts with an effector/target protein.
  • This interaction leads to the production of second messengers, resulting in signal amplification.
  • Enzyme targets produce many second messenger molecules after G-protein coupled receptor activation.

G Protein Subtypes and Their Effects

  • Gs:
    • αs subunit
    • Target: Adenylate cyclase
    • Effect: Increased cAMP
  • Gi:
    • αi subunit
    • Target: Adenylate cyclase
    • Effect: Decreased cAMP
  • Gq:
    • αq subunit
    • Target: Phospholipase C
    • Effect: Increased IP3, diacylglycerol, and cytoplasmic Ca^{2+}

Neurotransmitters and Receptor Types

  • Acetylcholine: Acts on both ligand-gated ion channels (LGIC) and GPCRs.
  • Noradrenaline, Dopamine, Neuropeptides: Act on GPCRs.
  • Serotonin, Glutamate, GABA: Act on both LGICs and GPCRs.
  • There are over 800 different GPCRs, which play wide range of roles in the nervous system, vision, and olfaction.

Neurotransmitters

  • Types of neurotransmitters include:
    • Amines: Dopamine, serotonin, adrenaline, noradrenaline, histamine, acetylcholine
    • Neuropeptides: Substance P, endorphins, enkephalins, vasopressin, oxytocin
    • Amino acids: L-glutamate, γ-aminobutyric acid (GABA), glycine
    • Others: Nitric oxide (NO), adenosine, ATP
  • Dale’s Principle is mentioned.

Criteria for Neurotransmitter Identification

  • A neurotransmitter candidate must meet the following criteria:
    • Must be synthesized by the neuron.
    • Must be present in the synaptic terminal at sufficient concentrations.
    • Must be released upon (pre)synaptic stimulation.
    • Exogenous application to the postsynaptic cell evokes a response.
    • A mechanism must exist for its removal from the synaptic cleft.

Cholinergic Terminal

  • Choline + Acetate are used to create Acetylcholine.
  • Acetyl CoA + Choline creates ACh + CoA.
  • ACh is removed from the synaptic cleft via Acetylcholinesterase (AChE).

Glutamate-Glutamine Cycle

  • Glutamate (Glu) is converted to glutamine (Gln) by glutamine synthetase in astrocytes.
  • Glutamine is then transported back to neurons.
  • In neurons, glutaminase converts glutamine back to glutamate.
  • Key elements:
    • EAAT: Excitatory Amino Acid Transporter
    • VGluT: Vesicular Glutamate Transporter
    • GlnT: Glutamine Transporter

Transmitter/Receptor Systems: Cholinergic Transmission

  • Acetylcholine receptors are divided into two main types: nicotinic and muscarinic.
    • Nicotinic: Ionotropic, pentameric (5 subunits), with 16 subunits in humans (9 α, 4 β, γ, δ, ε), contains 2 ACh binding sites, built-in cation channel
    • Muscarinic: Metabotropic (GPCR), monomeric, M1-5 subtypes, 1 ACh binding site influences K^+ permeability

M Type K^+ Channel

  • ACh is released.
  • Activation proceeds until threshold is reached.
  • M type K^+ channel activation is illustrated.

Transmitter/Receptor Systems: Glutamatergic Transmission

  • Glutamate receptors include both ligand-gated ion channels (iGluR) and GPCRs (mGluR).
    • iGluRs: AMPA (Quisqualate), Kainate, NMDA (fast)
    • mGluRs: Group 1 (mGluR1,5), Group 2 (mGluR2,3), Group 3 (mGluR4,6,7,8) (slower)

NMDA Receptors

  • NMDA receptors are special due to:
    • High permeability to Ca^{2+}, blocked by Mg^{2+} at resting membrane potential (RMP).
    • Requirement for glycine (or D-serine) as a co-agonist.

Magnesium Block of the NMDAR

  • At -70 mV, Mg^{2+} blocks the channel.
  • At -30 mV, the block is relieved, allowing Na^+, Ca^{2+} and K^+ to flow through.

Role of AMPA and NMDA Receptors in Depolarization and Synaptic Strengthening

  1. Current flow induced by AMPA receptor activation leads to local depolarization.
  2. This depolarization transmits to the soma.
  3. Local depolarization deinactivates the NMDA receptor, greatly increasing depolarization and influx of Ca^{2+}.
  4. This transmits to the soma.
  5. mGluR1 activation causes long/slow depolarization, also lifting the Mg^{2+} block of the NMDA receptor, leading to more depolarization.
  6. The synapse may become strengthened with repeated use (long-term potentiation, LTP).

Transmitter/Receptor Systems: GABAergic Transmission

  • GABA receptors include ligand-gated chloride channels and GPCRs.
    • Ligand gated Chloride channels: GABAA/C (fast, pentamers, many different subunits)
    • GPCRs (slower)

GABA Receptors

  • GABA binding to GABAA receptors:
    • Increases chloride permeability.
    • E{Cl} is often close to RMP, so tends to stabilize membrane potential close to E{Cl}.
    • Leads to hyperpolarization, inhibition.

GABAA Receptor Pharmacology

  • Illustrates various binding sites on the GABAA receptor for different drugs:
    • Agonist binding site: GABA, Muscimol
    • Picrotoxinin site
    • Barbiturate, propofol, etomidate site
    • Benzodiazepine, β-carboline site
    • Neurosteroid site

GABAB Receptors

  • GABAB receptors are found pre- or post-synaptically.
  • Composed of two subunits: GABAB1 and GABAB2.
  • Act to:
    • Inhibit voltage-gated Ca^{++} channels (inhibiting transmitter release).
    • Open potassium channels (reducing post-synaptic excitability).
    • Inhibit adenylyl cyclase.

Summary of Receptor Types and Associated Neurotransmitters

  • Ionotropic: Glutamate, GABA, Serotonin, Acetylcholine, ATP, Glycine
  • Both Ionotropic and Metabotropic: Acetylcholine, Serotonin, Glutamate, GABA
  • Metabotropic: Neuropeptides, Dopamine, Histamine, Adenosine, Noradrenaline, Adrenaline